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Bioisosteric Replacements of the Pyrazole Moiety of Rimonabant: Synthesis, Biological Properties, and Molecular Modeling Investigations of Thiazoles, Triazoles, and Imidazoles as Potent and Selective CB 1 Cannabinoid Receptor Antagonists
Abstract
Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.
... nists [11][12][13][14][15][16][17][18][19] , with triazole as a substituent in some compounds [20][21][22] . Of note, bicyclic 1,2,3-triazole derivatives have only been described by Di Marzo et al. ( I , Fig. 1 ) [23] and our previous study [24] . ...
Extending the click chemistry concept, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reac- tion was used to synthesize a series of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles using 1- (2-hydroxycyclohexyl)-4-dimethylaminomethyl 1,2,3-triazole (AMTC) as the Cu-binding ligand. The 1,4,5- trisubstituted 1,2,3-triazoles were obtained through 5-lithiation followed by a reaction with an elec- trophile. This study also showed, that a 1,4-disubstituted 5-lithiotriazole can be acylated using N,N- dimethylbenzamide, as an extension of the dimethylformamide formylation. The synthesized compounds, designed to mimic the bicyclic non-classical cannabinoids, were evaluated for their affinity to the cannabinoid type 1 receptor (CB 1 R). For a subset of 4-(3-hydroxycyclohexyl) 1,2,3-triazoles, the cis/trans relative configuration was determined, using 1D and 2D NMR combined with DFT-based chemical shift prediction.
... 37,[39][40][41] The molecular size and shape of pyrazole resemble those of thiazole and a previous study has revealed that thiazole could be a bioisostere to pyrazole. 42 Inspired by (i) these findings, (ii) the successfully approved pyrazole-containing anticancer kinase inhibitors, namely crizotinib (an anaplastic lymphoma kinase (ALK) inhibitor), erdafitinib (a fibroblast growth factor receptor (FGFR) inhibitor), encorafenib (a BRAF inhibitor), and pralsetinib (a rearranged during transfection (RET) inhibitor), 43 (iii) and the pyrazole-based CDK2 inhibitors in clinical trials, we designed and synthesised 4-(pyrazol-4-yl)pyrimidine-based CDK2 inhibitors by substituting the thiazole group of CDKI-73 with a pyrazole motif. Herein, we report the preparation and evaluation of 2-anilino-4-(1-methylpyrazol-4-yl)pyrimidine analogues as potential CDK2 inhibitors. ...
Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (K i = 0.023 and 0.001 μM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI 50 = 0.0250.780 μM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer. Keywords CDK2, CDK2 inhibitor, 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine, antiproliferative activity, bioisosteric replacement, CDKI-73 3
... 37,[39][40][41] The molecular size and shape of pyrazole resemble those of thiazole and a previous study has revealed that thiazole could be a bioisostere to pyrazole. 42 Inspired by (i) these findings, (ii) the successfully approved pyrazole-containing anticancer kinase inhibitors, namely crizotinib (an anaplastic lymphoma kinase (ALK) inhibitor), erdafitinib (a fibroblast growth factor receptor (FGFR) inhibitor), encorafenib (a BRAF inhibitor), and pralsetinib (a rearranged during transfection (RET) inhibitor), 43 (iii) and the pyrazole-based CDK2 inhibitors in clinical trials, we designed and synthesised 4-(pyrazol-4-yl)pyrimidine-based CDK2 inhibitors by substituting the thiazole group of CDKI-73 with a pyrazole motif. Herein, we report the preparation and evaluation of 2-anilino-4-(1-methylpyrazol-4-yl)pyrimidine analogues as potential CDK2 inhibitors. ...
Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (Ki = 0.023 and 0.001 μM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI50 = 0.025-0.780 μM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.
... Substituted imidazoles signify an imperative group of compounds establish in a huge figure of natural products and organically active compounds as anthelmintic [7], anticancer and antitumor agent [8,9], antifungal [10], antibacterial [11][12][13], antitubercular agent [14] and anti-inflammatory [15,16]. They perform as inhibitors for acetylcholine and butyrylcholine esterases [17], p38 MAP kinase [18], JNK inhibitor [19], B-Raf kinase [20] activin receptor-like kinase [21], cycloxygenase-2 inhibitors [22], glucagon receptors antagonist [23], Herbicides [24] and Plant growth regulator [25]. In recent years, ultrasonic radiation [26] for the synthesis of imidazole derivatives, microwave-assisted [27] procedures have previously been reported. ...
In the present study, we have been achieved effortless, highly adaptable multi-component synthesis of several biologically active imidazoles derivatives in single pot three components via means of the reaction of ammonium acetate, substituted aldehydes and benzyl using tartaric acid as an effective, highly efficient organocatalyst. The synthesis of all the compounds has been confirmed through elemental analysis, FTIR, 1HNMR, and 13C NMR. All of the produced imidazole derivatives were docked against a bacterial protein [glucosamine-6-phosphate synthase (GlcN-6-P)] which were obtained as of [RCSB protein data bank (PDB ID: 2VF5)] using Autodock-vina and obtained conformations of ligand complexes and proteins (PDB ID: 2VF5) were examined for binding energy and interactions of the docked arrangement via [Molegro Molecular Viewer 2.5 and Ligplot v.1.4.5]. The synthesized compounds were also checked for antimicrobial activities beside human pathogenic bacterial strains “Escherichia coli, Bacillus subtilis, Salmonella typhi, and Pseudomonas aeruginosa” by disk diffusion method by gentamicine reference and a negative control “DMSO”. Some of the Imidazole derivatives were found to have high antibacterial action against “Escherichia coli, Salmonella typhi, Bacillus subtilis”, and moderate activity against “Pseudomonas aeruginosa”.
... Studies have shown that modifying the rimonabant pyrazole CB1 pharmacophore could generate novel CB1 modulators [10]. A peripherally acting biarylpyrazole CB1 antagonist, namely, AM6545, developed in our laboratory, was shown to be a safer alternative to rimonabant for treating metabolic disorders [11][12][13]. AM6545, in vivo, has proven to be efficacious in animal models. AM6545 was largely restricted to the periphery, and unlike rimonabant, it behaved as a neutral antagonist when tested in CB1 cell lines and primary cell cultures [14]. ...
Background and Objectives: Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the present study. Materials and Methods: A 12-week high-fructose/high-salt feeding model of metabolic syndrome was used to induce IR in male Wistar rats. For this purpose, two different CB1-antagonists were synthesized and administered to the rats during the final four weeks of the study, AM6545, the peripheral neutral antagonist and AM4113, the central neutral antagonist. Results: High-fructose/salt feeding for 12 weeks led to development of IR while both AM6545 and AM4113, administered in the last 4 weeks, significantly inhibited IR. This was correlated with increased animal body weight wherein both AM6545 and AM4113 decreased body weight in IR animals but with loss of IR/body weight correlation. While IR animals showed significant elevations in serum cholesterol and triglycerides with no direct correlation with IR, both AM6545 and AM4113 inhibited these elevations, with direct IR/cholesterol correlation in case of AM6545. IR animals had elevated serum uric acid, which was reduced by both AM6545 and AM4113. In addition, IR animals had decreased adiponectin levels and elevated liver TNFα content with strong IR/adiponectin and IR/TNFα correlations. AM6545 inhibited the decreased adiponectin and the increased TNFα levels and retained the strong IR/adiponectin correlation. However, AM4113 inhibited the decreased adiponectin and the increased TNFα levels, but with loss of IR/adiponectin and IR/TNFα correlations. Conclusions: Both CB1 neutral antagonists alleviated IR peripherally, and exerted similar effects on rats with metabolic syndrome. They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral antagonists with improved safety profiles for managing metabolic disorders.
... Moreover, some molecules having pyrazole structure exhibited excellent properties such as antiviral [11], antioxidant [12], anti-inflammatory [13], antitumor [14] and antidepressant [15] activities. On the other hand, pyrazolecontaining compounds are widely commercialized such as Tartrazine [16], Fomepizole [17], Ceftolozane [18], Celebrex [19], Rimonabant [20] and Viagra [21]. Furthermore, substituted pyrazole molecules were used to ligand as a catalyst in the cross coupling reaction [22] and also was used α-Helix mimetic as inhibitors of protein-protein interactions [23]. ...
A series of substituted pyrazole compounds (1–8 and 9a, b) were synthesized and their structure was characterized by IR, NMR, and Mass analysis. These obtained novel pyrazole derivatives (1–8 and 9a, b) were emerged as effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) and acetylcholinesterase (AChE) enzymes with K i values in the range of 1.03 ± 0.23–22.65 ± 5.36 µM for hCA I, 1.82 ± 0.30–27.94 ± 4.74 µM for hCA II, and 48.94 ± 9.63–116.05 ± 14.95 µM for AChE, respectively. Docking studies were performed for the most active compounds, 2 and 5, and binding mode between the compounds and the receptors were determined.
... They are biologically active compounds having fungicidal [4], antiinflammatory [5], analgesic [6], antitumor [7] and antibacterial activities [8]. Substituted imidazoles are widely used as glucagon receptors [9], CB1 cannabinoid receptor antagonists [10] and modulators of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) agents [11]. It can also be employed as herbicides [12], fungicides and plant growth regulators [13]. ...
... Compounds such as 7c are not commonly encountered, but definitely have the potential to be of interest if explored further. The good physical chemical properties of thiazoles, as well as their ability to act as isosteres to thiophenes, carbonyls and pyrazoles [49,50] make this scaffold an intriguing novel motif. ...
The focus of this review is to provide an overview of the field of organocatalysed photoredox chemistry relevant to synthetic medicinal chemistry. Photoredox transformations have been shown to enable key transformations that are important to the pharmaceutical industry. This type of chemistry has also demonstrated a high degree of sustainability, especially when organic dyes can be employed in place of often toxic and environmentally damaging transition metals. The sections are arranged according to the general class of the presented reactions and the value of these methods to medicinal chemistry is considered. An overview of the general characteristics of the photocatalysts as well as some electrochemical data is presented. In addition, the general reaction mechanisms for organocatalysed photoredox transformations are discussed and some individual mechanistic considerations are highlighted in the text when appropriate.
... Development of new multi-component reactions (MCRs) [1], in particular for the synthesis of polysubstituted imidazoles is an important area of research in medicinal chemistry. The imidazoles exhibit a wide spectrum of biological activities [2][3][4][5][6][7][8][9][10][11][12][13][14]. The 1,2,4, imidazoles are present in many biological systems and drug molecules such as olmesartan, medoxomil, losartan, eprosartan and trifenagrel [15,16]. ...
2-(4-Bromophenyl)-1-(3-chloro-2-methylphenyl)- 4,5-diphenyl-1 H -imidazole ( 1 ) and 1-(3-chloro-2-methylphenyl)-2-(4-chlorophenyl)-4,5-diphenyl-1 H -imidazole ( 2 ) were synthesized by one-pot four-component reactions. These compounds crystallize in the monoclinic crystal system with the space group P 2 1 / n . The crystal structures were solved by direct methods and refined by a full matrix least squares procedure to a final R value of 0.0572 ( 1 ) and 0.0588 ( 2 ) for 2748 and 2278 observed reflections, respectively. Molecular docking studies were implemented to understand the inhibitory activity of related compounds against glucosamine 6-phosphate (GlcN-6-P) synthase, the target protein for the antimicrobial agents.
... In the literature, tacrine hybrids are characterized as a new paradigm to treat Alzheimer's disease [140]: homodimers hybrids, heterodimers hybrids, tacrine-4-oxo-4Hchromene [141], tacrine-melatonin hybrids [142,143], tacrineimidazole hybrids [144,145], tacrine-xanomeline hybrids [146], tacrine-donepezil hybrids [147], tacrine-oxoisoaporphine hybrids [148], tacrine-huperzine hybrids [149], tacrineebselen hybrids [150,151], tacrine-lipoic acid hybrid [152], tacrine-ferulic acid hybrid [153], tacrine-trolox hybrids [154], tacrine-m-(trimethylammonio)trifluoroacetophenone hybrids e.g. [155] and tacrine-6 hydrazinonicotinamide [156]. ...
Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as model inhibitor of cholinesterases in the therapy of Alzheimer's disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer's disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist a new paradigm to treat Alzheimer's disease. We have also reported potential of these analogues in the treatment of Alzheimer's diseases in various experimental systems.
... Tetra substituted imidazoles are very important heterocyclic compounds in pharmaceutical and biochemical processes [2], and are biologically active compounds having fungicidal [3], anti-inflammatory [4], analgesic [5], antitumor [6] and antibacterial activities [7]. Members of this class also act as inhibitors of p38 mitogen-activated protein kinase [8], B-Raf kinase [9], transforming growth factor β 1 receptor type 1 [10], biosynthesis of interleukin-1 [11], and cyclooxygenase-2 [12]. Substituted imidazoles are widely used as glucagon receptors [13], CB1 cannabinoid receptor antagonists [14] and modulators of P-glycoprotein mediated multidrug resistance agents [15]. ...
Heterocyclic compounds have potential applications in many fields of life. We synthesized novel tetra substituted imidazoles by four-component condensation of benzil, substituted aldehydes, substituted anilines and ammonium acetate as a source of ammonia and acetic acid as the solvent. Their chemical structures were resolved through X-ray crystallographic and spectroscopic (Fourier transform IR and UV–vis) techniques. In addition to experimental analysis, density functional theory (DFT) calculations at the B3LYP/6-311 + G(d,p) level were performed on 4-bromo-2-(1-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole-2-yl)phenol (1), 4-bromo-2-(1-(1-naphthalen-yl)-4,5-diphenyl-1H-imidazole-2-yl)phenol (2), and 2-(1-(2-chlorophenyl)-4,5-diphenyl-1-H-imidazole-2-yl)-6-methoxyphenol (3) to obtain the optimized geometry and spectroscopic (Fourier transform IR and UV–vis) and non-linear optical properties. Frontier molecular orbital analysis was performed at the Hartee-Fock/6-311+g(d,p) and DFT/B3LYP/6-311+G(d,p) levels of theory. Natural bond orbital (NBO) and UV–vis spectral analyses were performed at the M06-2X/6-31+G(d,p) and time-dependent DFT/B3LYP/6-311+G(d,p) levels, respectively. Overall, the DFT findings show good agreement with the experimental data. The hyper conjugative interaction network, which is responsible for the stability of compounds 1, 2 and 3 was explored by the NBO approach. The global reactivity parameters were explored with use of the energy of the frontier molecular orbitals. DFT calculations predict the first-order hyperpolarizabilities of compounds 1, 2 and 3 are 294.89 × 10⁻³⁰, 219.45 × 10⁻³⁰ and 146.77 × 10⁻³⁰ esu, respectively. A two-state model was used to describe the non-linear optical properties of the compounds investigated.
... Plenty of interesting and useful annulated heterocyclic systems have been synthesized using hydrazine and its derivatives; one of these derivatives is cyanoacetic acid hydrazide that can condense with various carbonyl compounds to afford the corresponding hydrazones. The urgent and insisting need for synthesis of new heterocyclic compounds related to the named hydrazide such as thiophenes, azines and coumarins is due to their pharmalogical actions; these compounds could be used as antimicrobial [1,2], antitubercular [3,4], anticonvulsant [5,6] antiinflammatory [7,8], antidepressant [9], antitumor [10], and analgesic activities [11]. In addition, pyridinecarbonitriles have been known to posses antihypertensive [12], antihistaminic [13], anticancer [14], in addition to antibacterial [15][16][17] or antifungal actions [16][17][18]. ...
The reaction of 2-cyano-N'-(1-(naphthalen-2-yl)ethylidene)acetohydrazide 1 with the aromatic aldehydes afforded the corresponding arylidene derivatives 3a-e. Refluxing of the latter product 3a with hydrazine hydrate gave the aminopyrazole derivative 4. Compound 1 was utilized as key intermediate for the synthesis of some new 1,2-dihydropyridine 7 and 2,3-dihydrothiazole 8 derivatives. Treatment of 8 with triethylorthoformate in acetic anhydride yielded 2,3-dihydrothiazolo[4,5-d]pyrimidinone 9. Moreover, reaction of 1 with phenyl isothiocyanate gave the corresponding thioacetanilide 10. The latter compound 10 was used for the synthesis of thiadiazole 12. The structures of all new compounds were elucidated on the basis of elemental analysis and spectral data. Twelve of the synthesized products were evaluated as antifungal agents.
... These molecules have great importance due to their useful biological and pharmacological aspects. They act as inhibitors of p38 MAP kinase (Vatter, 1994), B-Raf kinase (Takle, 2006), transforming growth factor b1 (TGF-b1) type 1 actin receptorlike kinase (ALK5) (Khanna, 1997), cyclooxygenase-2 (COX-2) (Lange, 2005) and biosynthesis of interleukin-1 (IL-1) (Gallagher, 1995). Suitably substituted imidazoles are expansively used as glucagon receptors (De Laszlo, 1999) and CB1 cannabinoid receptor antagonists (Eyers, 1998), modulators of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) (Newman, 2000), antitumor (Wang, 2002) and Antibacterial agents (Antolini, 1999). ...
A green and efficient method, using Hemoglobin and Ferrous ammonium sulphate was developed for the synthesis of 2,4,5-triaryl-1H-imidazoles devoid of solvent. The synthesized compounds were characterized by spectral analyses.
... [3] Various derivatives of imidazoles are used as anti-bacterial, [4] anti-tumoral, [5] anti-inflammatory, [6] fungicidal, antimycotic, anti-ulcerative, antibiotic and analgesic [7] agents, herbicides and plant growth regulators. [2] Additionally, they are also used as inhibitors of p38 MAP kinases, [8] B-Raf kinases, cyclooxygenase-2, transforming growth factor b1, type-1 activin receptor-like kinase, [9][10][11] in IL-1 biosynthesis, [12] as therapeutic agents, glucagon receptors, [13] heme oxygenase-1 inhibitors, heme oxygenase inhibitors, fatty acid amide hydrolase inhibitors [14] and as photosensitive compounds in photography. [15] Further, they are also found as a core structural skeleton in many important biological compounds like histidine, histamine and biotin and in other drug moieties like trifenagrel, eprosartan and losartan. ...
A simple, highly efficient and green synthesis of 2,4,5-trisubsituted and 1,2,4,5-tetrasubstituted imidazoles was developed using a novel MCS-GT@Co(II) magnetically recoverable and recyclable catalyst under refluxing conditions with ethanol as a solvent. The catalyst was prepared by immobilization of chitosan onto Fe3O4 using glutaraldehyde as crosslinker followed by Co(II) ion immobilization via cobalt acetate. The catalyst was characterized using various techniques. For organic products determination, ¹H NMR, ¹³C NMR and Fourier transform infrared spectroscopies were used. The reaction was also tried with individual components of the catalyst, but the synergistic effect of the components in the prepared catalyst showed the highest yield and shortest reaction time.
In this study, several imidazole derivatives in one pot multicomponent reaction from various aldehydes (1(a‐z)), 9,10‐phenanthrenequinone, or benzyl (2), and ammonium acetate (3) were synthesized in the presence of acetic acid (AcOH) under reflux conditions at 120°C. Also, the photochromic properties of synthesized compounds were investigated in AcOH as a solvent under laboratory conditions at a temperature of 120°C. Moreover, the antibacterial and antioxidant activity of the synthesized compounds was investigated. The structure of the products was confirmed using FT‐IR, UV‐Vis, 1HNMR, and 13CNMR spectroscopy. The antimicrobial activity of these compounds against gram‐positive bacteria including Bacillus subtilis (B.s) and gram‐negative bacteria including Escherichia coli (E. coli) bacteria was evaluated by the well diffusion (WD) method, and the compounds 4o showed significant results for both antibacterial activity. To gain insight into how these compounds interact with two types of targets, i.e., human topoisomerase II alpha (5GWK) and acetylcholinesterase (7AIX), binding calculations have been used that provide significant results for both targets and show that most ligands can effectively bind to cleft nucleotides. Interfere in the first one or be well placed in them. Hydrophobic pocket in the dimension, which can ultimately lead to high scores achieved.
Simple pyrazoles are highly active bifunctional organocatalysts for alkyne–CO 2 carboxylation and are applicable to orthogonal tandem catalysis for the one-pot construction of various heterocycles, during which unexpected acyl migration is observed.
The present work emphasizes catalyst‐free 2,4,5‐tri‐ and 1,2,4,5‐tetra substituted imidazole synthesis using diversified aldehydes with benzil, ammonium acetate, or amines. Ammonium acetate plays a vital role as a reactant catalyst by dissociating into acetic acid to afford imine and diamine formation to ascertain the 2,4,5‐tri‐ and 1,2,4,5‐tetra substituted imidazoles. The key advantages of the current approach are efficient, greener, eco‐friendly, and facile, with moderate to excellent yield in shorter reaction time at the temperature of 80°C. Ethanol:water as a solvent makes the reaction process eco‐friendly. Overall, the described approach offers a promising route for the efficient and sustainable synthesis of substituted imidazoles, which have a wide range of applications in various fields, including pharmaceuticals, agrochemicals, and materials science.
Herein, we report an efficient DTBP promoted and NaI-catalyzed, greener protocol for the synthesis of highly substituted pyrazoles via C(sp²)–H bond functionalization. This protocol is general and the reaction efficacy improves significantly with the combined use of solvents t-BuOH and EtOH, producing a vast variety of substituted pyrazoles in good to excellent yields. The mechanistic investigations including the radical trapping experiment indicating the in-situ generation of intermediate free-radical species followed by intramolecular oxidative C–N bond formation afforded the desired pyrazole moiety. The synthetic versatility of this methodology is further highlighted by preparing a diverse range of substrates including di-/tri-/and tetra-substituted pyrazoles, and applying the methodology in the practical synthesis of bioactive scaffolds.
A simple protocol for the noble-metal-free oxidative cyclization of enamines and tBuONO has been developed. This KI-mediated formal [4 + 1] cycloamination reaction provides a practical strategy for the synthesis of imidazole-4-carboxylic derivatives using tBuONO both as an aminating reagent and oxidant. The reaction features wide substrate scope and good functional tolerance for enamine compounds, even the unactivated ones.
1,5-diarylpyrazoles were synthesized by a two-step procedure starting from hex-1-en-3-uloses. The initial microwave-assisted oxidative Heck type C-glycosylation of hex-1-en-3-uloses with arylboronic acids in the presence of Pd(OAc)2 and DDQ afforded C-1 aryl enones. The resulting product further reacted with arylhydrazines in the presence of InCl3 and oxygen to give the 1,5-diarylpyrazoles in moderate to good yields (51–83%).
Chemists found Imidazole as a multipurpose nucleus, primarily notable for its biological role in drug discovery. This compilation of the reports gives information regarding the development and the previous background of the synthesis of the nucleus. However, the synthesis through multicomponent is taken to narrow the report. The importance of the multicomponent reactions with many nucleus has been part of the heavy literature; however, the synthesis of the bioactive scaffold as imidazole has been highlighted here with the essential points. The emphasis of the review is to show the multicomponent approach where the multicomponent reaction plays a vital role in the formation of the ring. The MCR approaches align with modern‐day drug discovery, where the library of the molecules is needed for drug development within a limited time frame. The multicomponent also comes under the green chemistry, where the reaction time and fewer reactions step plays a crucial role.
Aim
To synthesize Oxadiazole, Imidazole, Benzimidazole, and Cyclohexano Analogues of 1, 5-benzodiazepines through phenoxyl/phenylamino linkage
Background
It is worthwhile to mention that Imidazoles, benzimidazoles, oxadiazoles, are analysed extensively mainly as per their ready availability, broad chemical reactivity, and wide spectrum of biochemical activities, like antimicrobial, anti-inflammatory, antitumor, anticonvulsant drugs, anti-tubercular medicines, and having anti-HIV effect etc.
Objective
The Oxadiazole, Imidazole, Benzimidazole derivatives were synthesized via Cyclohexano Analogues of 1, 5-benzodiazepines through phenoxyl/phenylamino linkage.
Method
The characteristic drift of our interest towards these molecules prompted us to think about the structural modification of [1, 5]-benzodiazepine compound by incorporating on its 2-position imidazole, benzimidazole, oxadiazole, nuclei through an aminophenyl or phenoxyl bridge to synthesize these novel heterocyclic analogues of 1, 5-benzodiazepines.
Results
These derivatives have been analysed by various spectrophometric techniques like UV, IR, NMR, and MS. The synthesis of these compounds via the mentioned methods are unique as Cyclohexano Analogues of 1, 5-benzodiazepines through phenoxyl/phenylamino is a totally new way of synthesis. The derivatives can be analysed for various properties in chemistry and pharmacology, as their parent compounds has many pharmacological properties.
Conclusion
The synthesis of these types of compounds does provide a new hope to medicinal and pharmaceutical industries. Therefore further efforts should be taken into consideration for their synthesis and analysis of their medicinal properties.
The dawn of the 21st century has brought a surge of imidazole-related synthetic approaches to design safe, less toxic, and efficient drug candidates. The ubiquitous nature and possibilities of the wide functionality of imidazole scaffolds have fascinated researchers in the field of drug design and discovery. The unique structural features and the ability of various biophysical interactions with proteins in the living system make imidazole analogs more captivating in medicinal chemistry. Due to their special characteristics, they bear an extensive range of therapeutic activities including antiparasitic, anti-Alzheimer, antiinflammatory, antidiabetic, antihypertensive, antidepressant, anticonvulsant, antihelminthic, anticoagulant, antiprotozoal, and antiulcer. In addition, imidazole-based compounds are proton pump inhibitors, receptor antagonism, hormone modulators, immune-modulators, and lipid level modulators that make them crucial for the design and development of new bioactive materials. In the new millennium, numerous studies have concentrated on the synthetic, therapeutic, and pharmacokinetic studies of imidazole-based pharmacophores. The present chapter aims to examine and analyze several biological activities of imidazoles against various fatal diseases and disorders. This systematic, comprehensible, and critical study is intended to be helpful for future scientists to uncover the enormous potential of imidazole scaffolds.
The structures of novel cocrystals of 4-nitropyridine N -oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide–4-nitropyridine N -oxide (1/1), C 5 H 4 N 2 O 3 ·C 6 H 6 N 2 O 4 S, and 4-chlorobenzenesulfonamide–4-nitropyridine N -oxide (1/1), C 6 H 6 ClNO 2 S·C 5 H 4 N 2 O 3 , are stabilized by N—H...O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N -oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N -oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N—H...O( N -oxide) and N—H...O(nitro) bridges. We present here a more detailed analysis of the N -oxide–sulfonamide–nitro N—H...O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N -oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.
Synthesis of (3, 5-dimethyl-1H-pyrazol-1-yl)(phenyl)-methanones in excellent yields by CBr4 mediated intermolec- ular cyclization of benzohydrazide and pentane-2, 4-dione has been reported. The method shows various advantages such as mild conditions, good functional group tolerance, environmental friendliness, easy operation with cheap reagents, step econo- my and can be scaled-up, offering a useful and attractive strategy to synthesize N-acylpyrazoles, which is widely presented in drugs, biologically active molecules and pesticides.
The cannabinoid receptor 2 (CB2 receptor) has attracted considerable interest, mainly due to its potential as a target for therapeutics for treating various diseases that have a neuroinflammatory or neurodegenerative component while avoiding the adverse psychotropic effects that accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this research, we are interested in the discovery of new chemotypes as highly selective CB2 modulators, which may serve as good starting points for further optimization towards the development of CB2 therapeutics. In search of new chemotypes as CB2 selective agents, we screened a series of triazole derivatives with interesting bioactive scaffolds, which led to the discovery of two novel and highly selective ligands for CB2 receptors. Compounds 6 and 11 produced a concentration-dependent inhibition of specific [³H]-CP55,940 (CB2) binding with Ki ± SEM values of 105.3 ± 22.6 and 116.4 ± 19.5 nM, respectively, while no binding affinity towards CB1 receptors or opioid receptors was observed. The CB2 functional activity of 6 and 11, as measured by a GPCR Tango assay (G-protein independent β-arrestin translocation assays), revealed that these compounds act as CB2 agonists with EC50 values ± SEM of 1.83 ± 0.16 and 1.14 ± 0.52 µM, respectively. Molecular modeling results showed that both compounds fit well into the active site of the CB2 receptor and showed strong hydrophobic interactions with key residues. In conclusion, the new triazole derivatives (6 and 11) showed promising activity towards CB2 receptors and have great potential to be developed into therapeutically useful CB2 agonist through hit-to-lead optimization.
In this work, we report the synthesis of functionalized hollow magnetite spheres (HMS) which were synthesized through gas-bubble assisted Ostwald ripening approach and post-functionalized with sulfamic acid groups. The fabricated material was used as an efficient solid-acid catalyst for one-pot three-component synthesis of medicinally important tri-substituted imidazoles under ultrasonic irradiation. Some of the striking features of the present protocol over existing routes are environmentally benign synthesis, milder reaction conditions, excellent yields, high selectivity, short reaction times, use of ultrasound as green energy source, less waste generation and effortless magnetic recovery and recycling of the catalyst. Further, the synthesized magnetite spheres extend the scope of ‘double functionalization’, i.e., the acidic groups can be immobilized on both internal and external surfaces which provides high acid loading as compared to previously reported solid supports.
Available online The palladium-catalysed cyclisation of propargylic electrophiles with nucleophiles represents a useful synthetic approach for the rapid construction of heterocyclic building blocks. However, these cyclisation reaction processes often pose a number of challenges due to the need for the simultaneous control of chemo-, regio- and stereoselectivity. Herein, we disclose the discovery of α-amido malonates as novel bis-nucleophiles in the highly chemo- and regioselective, as well as moderately enantioselective, palladium-catalysed cyclisation with propargylic compounds to afford a broad range of functionalised dihydrooxazine heterocycles. The new dihydrooxazine products will expand the suite of heterocycles available to medicinal chemists, and prompt the investigation of unchartered bis-nucloeophiles in palladium-catalysed cyclisation reactions en route to novel classes of heterocycle.
In recent years, severe viral infections have emerged, and antiviral chemotherapeutic agents are not adequately effective in curing these infections, leading to serious human diseases and loss of life. Consequently, a novel antiviral is urgently needed, which undoubtedly essential for the therapy of various fatal and debilitating viral infections. 1,2,4‐Triazole derivatives occupy a pivotal position in modern medicinal chemistry and have been incorporated in numerous clinical drugs, including antiviral drugs. To my best knowledge, there are few review articles exclusively handling 1,2,4‐triazole scaffold with the antiviral potential. This review aims to figure out recent perspectives and advances of 1,2,4‐triazole nucleus roles in various kinds of antiviral agents over the past decade, with some examples of rational design and some structure‐activity relationships. This review will hopefully provide perception into especially powerful compounds as lead structures and help in the rational design and development of novel 1,2,4‐triazole‐based compounds with strong anti‐virus efficacy.
The phytocannabinoid Δ9-tetrahydrocannabinol (THC) was isolated and synthesized in the 1960s. Since then, two synthetic cannabinoids (SCBs) targeting the cannabinoid 1 (CB1R) and 2 (CB2R) receptors were approved for medical use based on clinical safety and efficacy data: dronabinol (synthetic THC) and nabilone (synthetic THC analog). To probe the function of the endocannabinoid system further, hundreds of investigational compounds were developed; in particular, agonists with (1) greater CB1/2R affinity relative to THC and (2) full CB1/2R agonist activity. This pharmacological profile may pose greater risks for misuse and adverse effects relative to THC, and these SCBs proliferated in retail markets as legal alternatives to cannabis (e.g., novel psychoactive substances [NPS], “Spice,” “K2”). These SCBs were largely outlawed in the U.S., but blanket policies that placed all SCB chemicals into restrictive control categories impeded research progress into novel mechanisms for SCB therapeutic development. There is a concerted effort to develop new, therapeutically useful SCBs that target novel pharmacological mechanisms. This review highlights the potential therapeutic efficacy and safety considerations for unique SCBs, including CB1R partial and full agonists, peripherally-restricted CB1R agonists, selective CB2R agonists, selective CB1R antagonists/inverse agonists, CB1R allosteric modulators, endocannabinoid-degrading enzyme inhibitors, and cannabidiol. We propose promising directions for SCB research that may optimize therapeutic efficacy and diminish potential for adverse events, for example, peripherally-restricted CB1R antagonists/inverse agonists and biased CB1/2R agonists. Together, these strategies could lead to the discovery of new, therapeutically useful SCBs with reduced negative public health impact.
An efficient one-flask cascade method for synthesis of the multi-substituted 1,2,4-triazoles via chlorotrimethylsilane as a promoter was developed. Firstly, nitrilimines were transformed to hydrazonamides as intermediate in high yield by treatment with commercially available hexamethyldisilazane. Subsequently, the mixture was added with corresponding acyl chloride and heated in the presence of pyridine to give the corresponding multi-substituted 1,2,4-triazoles via chlorotrimethylsilane promoted heterocyclization reaction. The utility of method was demonstrated to synthesize CB1 ligands including Rimonabant analogue 4c and LH-21 3 for modeling study. All synthesized compounds were subjected to the cAMP functional assay of CB1/CB2 receptor. Especially, compound 4g enhanced the reversal of cAMP reduction by CP59440 than LH-21 and Rimonabant analogue in CHO-hCB1 cells. In addition, the docking results showed compound 4g fits the best position with CB1 receptor. However, the ability to penetrate brain-blood barrier of compound 4g is similar with Rimonabant in MDCK-mdr1 permeability assay, which might cause CNS side effect. This study still provides the basis for further development of a potent and specific CB1 antagonist.
Herein, direct N,N-dialkylation of acylhydrazides using alcohols is reported. This catalytic protocol provides one-pot synthesis of both symmetrical and unsymmetrical N,N-disubstituted acylhydrazides using an assortment of primary and secondary alcohols with remarkable selectivity and excellent yields. Interestingly, the use of diols resulted in intermolecular cyclization of acylhydrazides, and such products are privileged structures in biologically active compounds. Water is the only byproduct, which makes this catalytic protocol sustainable and environmentally benign.
Pyrazoles represent a significant class of heterocyclic compounds that exhibit pharmacological properties. The present study aimed to investigate the antioxidant potential of pyrazol derivative compounds in brain of mice in vitro and the effect of pyrazol derivative compounds in the oxidative damage and toxicity parameters in mouse brain and plasma of mice. The compounds tested were 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazol (1a), 3,5-dimethyl-4-(phenylselanyl)-1H-pyrazole (2a), 4-((4-methoxyphenyl)selanyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (3a), 4-((4-chlorophenyl)selanyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4a), 3,5-dimethyl-1-phenyl-4-(phenylthio)-1H-pyrazole (1b), 3,5-dimethyl-4-(phenylthio)-1H-pyrazole (2b), 4-((4-methoxyphenyl)thio)-3,5-dimethyl-1-phenyl-1H-pyrazole (3b), 4-((4-chlorophenyl)thio)-3,5-dimethyl-1-phenyl-1H-pyrazole (4b), and 3,5-dimethyl-1-phenyl-1H-pyrazole (1c). In vitro, 4-(arylcalcogenyl)-1H-pyrazoles, at low molecular range, reduced lipid peroxidation and reactive species in mouse brain homogenates. The compounds also presented ferric-reducing ability as well nitric oxide-scavenging activity. Especially compounds 1a, 1b, and 1c presented efficiency to 1,1-diphenyl-2-picryl-hydrazyl-scavenging activity. Compounds 1b and 1c presented 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)-scavenging activity. In vivo assays demonstrated that compounds 1a, 1b, and 1c (300 mg/kg, intragastric, a single administration) did not cause alteration in the of δ-aminolevulinic acid dehydratase activity, an enzyme that exhibits high sensibility to prooxidants situations, in the brain, liver, and kidney of mice. Compound 1c reduced per se the lipid peroxidation in liver and brain of mice. Toxicological assays demonstrate that compounds 1a, 1b, and 1c did not present toxicity in the aspartate aminotransferase, alanine aminotransferase, urea, and creatinine levels in the plasma. In conclusion, the results demonstrated the antioxidant action of pyrazol derivative compounds in in vitro assays. Furthermore, the results showed low toxicity of compounds in in vivo assays.
We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of β-amyloid (Aβ), and Aβ self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).
Background:
Bioisosteric replacement is widely used in drug design for lead optimization. However, the identification of a suitable bioisosteric group is not an easy task.
Methods:
In this work, we present MolOpt, a web server for in silico drug design using bioisosteric transformation. Potential bioisosteric transformation rules were derived from data mining, deep generative machine learning and similarity comparison. MolOpt tries to assist the medicinal chemist in his/her search for what to make next.
Results and discussion:
By replacing molecular substructures with similar chemical groups, MolOpt automatically generates lists of analogues. MolOpt also evaluates forty important pharmacokinetic and toxic properties for each newly designed molecule. The transformed analogues can be assessed for possible future study.
Conclusion:
MolOpt is useful for the identification of suitable lead optimization ideas. The MolOpt Server is freely available for use on the web at http://xundrug.cn/molopt.
Transition-metal-catalyzed programmed sequential arylation reactions of 2-chloro-4-nitro-1H-imidazole were achieved. The methods are general and were applied in a chemoselective manner for the synthesis of different multiarylated 4-nitroimidazoles bearing three different...
Multicomponent Reactions (MCRs) have emerged as an efficient and eco-safe approach in organic synthesis. The influential nature of this approach has been well established in the fields of drug discovery, catalysis, material science, pharmaceutical and combinatorial chemistry. Not surprisingly, the development of multicomponent reactions leading to 1,2/1,3-azoles has expanded rapidly over the last few years. Despite their myriad synthetic applications, there is yet no exclusive review on the MCRs concerning the synthesis of 1,2/1,3-azoles. Therefore, this critical review covers the journey of MCRs to 1,2/1,3-azoles, including the reaction conditions, scope, and rationale behind the choice of catalyst as well as the proposed mechanism.
A novel and convenient one-pot synthesis of 3-amino-2H-1,2,4-triazoles from two molecules of isoselenocyanates and hydrazine hydrate via cyclodeselenisation was developed. Various 3-amino-2H-1,2,4-triazoles were obtained in moderate to good yields (33-45%, based on isoselenocyanates). The selenium powder and aromatic amine side products during the reaction could be recycled for efficient preparation of isoselenocyanates, which improved the atom economy. A plausible mechanism was proposed for the formation of the target products.
While life expectancy increases worldwide, treatment of neurodegenerative diseases such as AD becomes a major task for industrial and academic research. Currently, a treatment of AD is only symptomatical and limited to an early stage of the disease by inhibiting AChE. A cure for AD might even seem far away. A rethinking of other possible targets is therefore necessary. Addressing targets that can influence AD even at later stages might be the key. Even if it is not possible to find a cure for AD, it is of great value for AD patients by providing an effective medication. The suffering of patients and their families might be relieved and remaining years may be spent with less symptoms and restrictions. It was shown that a combination of hCB2R agonist and BChE inhibitor might exactly be a promising approach to combat AD. In the previous chapters, a first investigation of dual-acting compounds that address both hCB2R and BChE was illustrated (figure 6.1). A set of over 30 compounds was obtained by applying SARs from BChE inhibitors to a hCB2R selective agonist developed by AstraZeneca. In a first in vitro evaluation compounds showed selectivity over hCB1R and AChE. Further investigations could also prove agonism and showed that unwanted off-target affinity to hMOP receptor could be designed out. The development of a homology model for hCB2R (based on a novel hCB1R crystal) could further elucidate the mode of action of the ligand binding. Lastly, first in vivo studies showed a beneficial effect of selected dual-acting compounds regarding memory and cognition. Since these first in vivo studies mainly aim for an inhibition of the BChE, it should be the aim of upcoming projects to proof the relevance of hCB2R agonism in vivo as well. In addition, pharmacokinetic as well as solubility studies may help to complete the overall picture. Currently, hybrid-based dual-acting hCB2R agonists and selective BChE inhibitors are under investigation in our lab. First in vitro evaluations showed improved BChE inhibition and selectivity over AChE compared to tacrine.78 Future in vitro and in vivo studies will clarify their usage as drug molecules with regard to hepatotoxicity and blood-brain barrier penetration. Since the role of hCB2R is not yet completely elucidated, the use of photochromic toolcompounds becomes an area of interest. These tool-compounds (and their biological effect) can be triggered upon irradiation with light and thus help to investigate time scales and ligand binding. A set of 5-azobenzene benzimidazoles was developed and synthesized. In radioligand binding studies, affinity towards hCB2R could be increased upon irradiation with UV-light (figure 6.2). This makes the investigated compounds the first GPCR ligands that can be activated upon irradiation (not vice versa). The aim of upcoming research will be the triggering of a certain intrinsic activity by an “efficacy-switch”. For this purpose, several attempts are currently under investigation: an introduction of an azobenzene moiety at the 2-position of the benzimidazole core already led to a slight difference in efficacy upon irradiation with UV light. Another approach going on in our lab is the development of hCB1R switches based on the selective hCB1R inverse agonist rimonabant. First in vitro results are not yet available (figure 6.3).
The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promising targets for pharmacotherapy in the later stages of Alzheimer’s disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted μ-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.
Pentachloropyridine N -oxide, C 5 Cl 5 NO, crystallizes in the monoclinic space group P 2 1 / c . In the crystal structure, molecules are linked by C—Cl...Cl halogen bonds into infinite ribbons extending along the crystallographic [100] direction. These molecular aggregates are further stabilized by very short intermolecular N -oxide– N -oxide interactions into herringbone motifs. Computations based on quantum chemistry methods allowed for a more detailed description of the N -oxide– N -oxide interactions and Cl...Cl halogen bonds. For this purpose, Hirshfeld surface analysis and the many-body approach to interaction energy were applied.
A catalyst based on the readily available Cu2S/TMEDA system using a stable copper(I) source was developed for the Chan-Lam cross-coupling reaction. The capability of the catalyst was demonstrated with 1H-benzo[d]imidazol-2(3H)-one, 1H-benzo[d]imidazole, and 1H-imidazole together with electron-deficient, electron-rich, and sterically demanding boronic acids at room temperature in the presence of atmospheric oxygen to give the cross-coupling products in moderate to excellent yields. In addition, the coupling reaction of 1H-benzo[d]imidazole with several pinacol or neopentylglycol boronates indicated further potential of the catalyst. The reaction conditions tolerate the hydroxyl and bromo functional groups. The catalytic system also enables to synthesize the mono-N-substituted anilines from primary aliphatic amines. However, the two model compounds for the secondary and aromatic amines, piperidine and aniline, do not react. Two sterically demanding products with the restricted CN bond rotation, synthesized by the N-arylation of 1H-benzo[d]imidazol-2(3H)-one with o-tolylboronic acid, enabled to confirm the atropisomers prepared by the Chan-Lam cross-coupling reaction. Furthermore, an example of one-pot Chan-Lam and Suzuki-Miyaura reaction has been reported.
A silver‐catalyzed aerobic oxidative [3+2] cycloaddition of azomethine ylides with aryl or heteroaryl isocyanides has been developed. The reaction represents a novel protocol for the efficient and practical synthesis of 1,2‐diarylimidazoles bearing a broad range of substituents in good to excellent yields under mild conditions. The practicability of this cycloaddition was shown by a gram‐scale synthesis and a double cycloaddition for the construction of highly conjugated polyarylimidazole systems.
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(-)-Δ⁹-Tetrahydrocannabinol ((-)-Δ⁹-THC) is the major active psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its derivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the neuronal cannabinoid receptor is found mostly in neuronal cells and tissues while CB2 or the peripheral cannabinoid receptor has been detected in spleen and in several cells of the immune system. It has previously been shown that activation of CB1 or CB2 receptors by cannabinoid agonists inhibits adenylyl cyclase activity. Utilizing Chinese hamster ovary cells and COS cells transfected with the cannabinoid receptors we report that(-)-Δ⁹-THC binds to both receptors with similar affinity. However, in contrast to its capacity to serve as an agonist for the CB1 receptor, (-)-Δ⁹-THC was only able to induce a very slight inhibition of adenylyl cyclase at the CB2 receptor. Morever, (-)-Δ⁹-THC antagonizes the agonist-induced inhibition of adenylyl cyclase mediated by CB2. Therefore, we conclude that (-)-Δ⁹-THC constitutes a weak antagonist for the CB2 receptor.
This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. The chairpersons were Appa Hungund and George Koob. The presentations were (1) Role of endocannabinoids in ethanol tolerance, by Appa Hungund; (2) Modulation of cannabinoid receptor and its signal transduction in chronic alcoholism, by B. S. Basavarajappa; (3) Endocannabinoid involvement in the control of appetitive behavior, by George Kunos; (4) Regulation of voluntary ethanol intake by cannabinoid receptor agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado Rodriguez de Fonseca; and (6) Endocannabinoids and dopamine interactions in vivo, by Loren Parsons and George Koob.
A cDNA clone encoding a receptor protein which presents all the characteristics of a guanine-nucleotide-binding protein (G-protein)-coupled receptor was isolated from a human brain stem cDNA library. The probe used (HGMP08) was a 600 bp DNA fragment amplified by a low-stringency PCR, using human genomic DNA as template and degenerate oligonucleotide primers corresponding to conserved sequences amongst the known G-protein-coupled receptors. The deduced amino acid sequence encodes a protein of 472 residues which shares 97.3% identity with the rat cannabinoid receptor cloned recently [Matsuda, Lolait, Brownstein, Young & Bronner (1990) Nature (London) 346, 561-564]. Abundant transcripts were detected in the brain, as expected, but lower amounts were also found in the testis. The same probe was used to screen a human testis cDNA library. The cDNA clones obtained were partially sequenced, demonstrating the identity of the cannabinoid receptors expressed in both tissues. Specific binding of the synthetic cannabinoid ligand [3H]CP55940 was observed on membranes from Cos-7 cells transfected with the recombinant receptor clone. In stably transfected CHO-K1 cell lines, cannabinoid agonists mediated a dose-dependent and stereoselective inhibition of forskolin-induced cyclic AMP accumulation. The ability to express the human cannabinoid receptor in mammalian cells should help in developing more selective drugs, and should facilitate the search for the endogenous cannabinoid ligand(s).
Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
The enteric nervous system of several species, including the mouse, rat, guinea pig and humans, contains cannabinoid CB1 receptors that depress gastrointestinal motility, mainly by inhibiting ongoing contractile transmitter release. Signs of this depressant effect are, in the whole organism, delayed gastric emptying and inhibition of the transit of non-absorbable markers through the small intestine and, in isolated strips of ileal tissue, inhibition of evoked acetylcholine release, peristalsis, and cholinergic and non-adrenergic non-cholinergic (NANC) contractions of longitudinal or circular smooth muscle. These are contractions evoked electrically or by agents that are thought to stimulate contractile transmitter release either in tissue taken from morphine pretreated animals (naloxone) or in unpretreated tissue (gamma-aminobutyric acid and 5-hydroxytryptamine). The inhibitory effects of cannabinoid receptor agonists on gastric emptying and intestinal transit are mediated to some extent by CB1 receptors in the brain as well as by enteric CB1 receptors. Gastric acid secretion is also inhibited in response to CB1 receptor activation, although the detailed underlying mechanism has yet to be elucidated. Cannabinoid receptor agonists delay gastric emptying in humans as well as in rodents and probably also inhibit human gastric acid secretion. Cannabinoid pretreatment induces tolerance to the inhibitory effects of cannabinoid receptor agonists on gastrointestinal motility. Findings that the CB1 selective antagonist/inverse agonist SR141716A produces in vivo and in vitro signs of increased motility of rodent small intestine probably reflect the presence in the enteric nervous system of a population of CB1 receptors that are precoupled to their effector mechanisms. SR141716A has been reported not to behave in this manner in the myenteric plexus-longitudinal muscle preparation (MPLM) of human ileum unless this has first been rendered cannabinoid tolerant. Nor has it been found to induce "withdrawal" contractions in cannabinoid tolerant guinea pig ileal MPLM. Further research is required to investigate the role both of endogenous cannabinoid receptor agonists and of non-CB1 cannabinoid receptors in the gastrointestinal tract. The extent to which the effects on gastrointestinal function of cannabinoid receptor agonists or antagonists/inverse agonists can be exploited therapeutically has yet to be investigated as has the extent to which these drugs can provoke unwanted effects in the gastrointestinal tract when used for other therapeutic purposes.
The primary psychoactive ingredient in cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions,
and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous
cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward
across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory,
cognition, and pain perception by means of this cellular mechanism.
Recent studies suggest that the endocannabinoid system modulates feeding. Despite the existence of central mechanisms for the regulation of food intake by endocannabinoids, evidence indicates that peripheral mechanisms may also exist. To test this hypothesis, we investigated (1) the effects of feeding on intestinal anandamide accumulation; (2) the effects of central (intracerebroventricular) and peripheral (intraperitoneal) administration of the endocannabinoid agonist anandamide, the synthetic cannabinoid agonist R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate (WIN55,212-2), and the CB1-selective antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A) on food intake in rats; and (3) the effects of sensory deafferentation on the modulation of feeding by cannabinoids. Food deprivation produced a sevenfold increase in anandamide content in the small intestine but not in the brain or stomach. Refeeding normalized intestinal anandamide levels. Peripheral but not central administration of anandamide or WIN55,212-2 promoted hyperphagia in partially satiated rats. Similarly, peripheral but not central administration of SR141716A reduced food intake. Capsaicin deafferentation abolished the peripheral effects of both cannabinoid agonists and antagonists, suggesting that these agents modulate food intake by acting on CB1 receptors located on capsaicin-sensitive sensory terminals. Oleoylethanolamide, a noncannabinoid fatty ethanolamide that acts peripherally, prevented hyperphagia induced by the endogenous cannabinoid anandamide. Pretreatment with SR141716A enhanced the inhibition of feeding induced by intraperitoneal administration of oleoylethanolamide. The results reveal an unexpected role for peripheral CB1 receptors in the regulation of feeding.
The cannabinoid CB(1) and CB(2) receptors belong to the Class A, rhodopsin-like family of G protein-coupled receptors. Antagonists for each receptor sub-type, as well as four structural classes of agonists that bind to both receptors, have been identified. An extensive amount of SAR has been developed for agonists and antagonists that bind at CB1, while the SAR of CB2 ligands is only now emerging in the literature. Cannabinoid agonists have been suggested to have potential therapeutic uses as appetite stimulants, analgesics, anti-emetics, anti-diarrheals, anti-spasmodics, tumor anti-proliferative agents, anti-glaucoma agents and as agents for the treatment of diseases associated with inappropriate retention of aversive memories such as post-traumatic stress disorders and phobias. Cannabinoid CB1 antagonists have been suggested to have potential therapeutic uses as appetite suppressants and as agents that improve memory. This review focuses first on recent CB1 and CB2 SAR and on the pharmacophores that have been developed for ligand recognition at the CB1 receptor. Emerging ideas about how the cannabinoid receptors are activated by agonists or inactivated by inverse agonists are then presented. Challenges for future SAR and pharmacophore development are also identified.
Purpose. To study oral absorption and brain penetration as a function of polar molecular surface area.
Methods. Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies.
Results. A linear relationship between brain penetration and dynamic polar surface area (Å2) was found (n = 45, R = 0.917, F1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 Å2. They can be tailored to brain penetration by decreasing the polar surface to <60−70 Å2. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules.
Conclusions. The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.
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On the basis of previous studies on synthetic models related to the antibiotic agents Netropsin and Distamycin-A, the design and synthesis of two potential DNA minor groove ligands are described. Methia-Nt and Isothia-Nt were prepared by liquid-phase peptidic synthesis from the key compounds ethyl 2-amino-5-methylthiazole-4-carboxylate (1) and ethyl 2-aminothiazole-5-carboxylate (8) respectively.
A convenient method has been developed for directly converting esters to amides using reagents derived from the reaction of trimethylaluminum with ammonium chloride, methylamine hydrochloride or dimethylamine hydrochloride.
Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and antioxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.
1H-1,2,4-Triazol-1-yl-propan-3-ones were synthesized regioselectively using a modified Mannich reaction. Reactions of enones and Mannich bases with imidazole are also described.
This article gives an overview of recent advances in the field of cannabinoid research, with an emphasis on patent literature. The review covers the period from January 2000 to July 2002. The period up to the year 2000 was previously reviewed by Goya and Jagerovic in this journal [1]. In addition to compounds acting directly at the cannabinoid receptor, recent advances in regulation of the endocannabinoid system are also discussed.
As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure−activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the 3-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a γ-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 receptor binding in vivo.
ADurch Einwirkung von Thionylchlorid auf die Enolacetate und Enol-methyläther einiger α-Ketosäuren wurden die entsprechenden Säurechloride dargestellt.
A cannabinoid receptor antagonist, SR144385, has been labeled with fluorine-18. [18F] SR144385 was synthesized in a multi-step reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18 labeled intermediate was deprotected and coupled with 1-aminopiperidine to give [18F]SR144385. The time for radiosynthesis, HPLC purification, and formulation was 2 hours from end-of-bombardment. [18F] SR144385 of high radiochemical purity was obtained at end-of-synthesis with an average (n=11) specific radioactivity of 1852 mCi/μmol and an average isolated, non-decay corrected radiochemical yield of 4% from potassium [18F] fluoride. Copyright © 1999 John Wiley & Sons, Ltd.
This chapter discusses the use of bioisosteric groups in lead optimization. The concept of bioisosteres refers to compounds or a substructure of compounds that share similar shapes, volumes, electronic distributions, and physiochemical properties, which together produce similar biological activities. It is difficult to clearly define the extent of similarity that is deemed necessary for consideration as a bioisostere. However, despite its ambiguity, medicinal chemists have widely adopted this concept for drug discovery efforts. Bioisosteric replacement is often explored for the lead compound to optimize the potency and selectivity or to improve the overall ADME profile. Sometimes, bioisosteres are used simply to circumvent previous patent coverage of leads in the literature. The chapter covers some of the recent successful bioisosteric replacement work in lead optimization in the literature. It includes some typical, yet unsuccessful, examples of bioisosteric replacements to demonstrate the principles and limitations of this technique. It also discusses the concept of conformational restriction, atom replacement, and heterocyclic ring replacements.
JMM and LAB). Key Words: Cannabinoid agonists—Cannabinoid antagonists—Cannabinoid receptors— CB 1 —CB 2 —∆ 9 -THC (∆ 9 -Tetrahydrocannabinol)—Marijuana—SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydro-chloride].
Mammalian tissues contain at least two types of cannabinoid receptor, CB₁, found mainly on neurones and CB₂, found mainly in immune cells. Endogenous ligands for these receptors have also been identified. These endocannabinoids and their receptors constitute the endogenous cannabinoid system. Two cannabinoid receptor agonists, Δ⁹-tetrahydrocannabinol and nabilone, are used clinically as anti-emetics or to boost appetite. Additional therapeutic uses of cannabinoids may include the suppression of some multiple sclerosis and spinal injury symptoms, the management of pain, bronchial asthma and glaucoma, and the prevention of neurotoxicity. There are also potential clinical applications for CB₁ receptor antagonists, in the management of acute schizophrenia and cognitive/memory dysfunctions and as appetite suppressants. Future research is likely to be directed at characterizing the endogenous cannabinoid system more completely, at obtaining more conclusive clinical data about cannabinoids with regard to both beneficial and adverse effects, at developing improved cannabinoid formulations and modes of administration for use in the clinic and at devising clinical strategies for separating out the sought-after effects of CB₁ receptor agonists from their psychotropic and other unwanted effects.
This chapter discusses cannabinoid drugs. Because of its psychotropic properties, Cannabis sativa was one of the first plants to be used by man, both in social-religious rites and in medicine. Many of the actions produced by Cannabis are undoubtedly distinct from the placebo effect, and in recent years, some have been confirmed in animals and in man. The chapter compares past use with modern data to present an overview of modern use and developments and to predict future pathways in medicinal chemistry research in this area. The following abbreviations are used: THC (tetrahydrocannabinol), CBD (cannabidiol), CBN (cannabinol), DMH (1,l-dimethylheptyl), SAR (structure–activity relationship), cisplatin (cis-diamminedichloroplatinum(II)), GABA (γ-aminobutyric acid), MES (maximal electroshock seizures), PTZ (pentylenetetrazol), AGS (audiogenic seizure), IOP (intraocular pressure). It is probably impossible for man today to comprehend fully the attitudes of an ancient population toward drugs and their associations with beliefs, religion, superstitions, and social life and interactions. Cannabis oil and leaf juice were employed externally for various skin diseases, wounds, and even in leprosy. The topical antibiotic properties of cannabinoids as known today justify the use in appropriate skin diseases. Cannabis was also used against vomiting. This use was widespread in India as well.
To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.
The syntheses, biological evaluations, and structure-activity relationships of a series of 4,5-bis-(4-methoxyphenyl)-2-substituted-thiazoles as potent antiplatelet agents with vasodilatory activity are described. 2-Guanidino-4,5-bis(4-methoxyphenyl)thiazole (3), designed from two parent compounds (itazigrel and timegadine), showed inhibitory activity of malondialdehyde (MDA, IC50 = 31 microM) production which is formed from the cyclooxygenase (CO)-catalyzed oxygenation of arachidonic acid in the synthesis of prostanoids in platelets, with vasodilatory activity (ED50 = 2.0 microM). Further structure-activity relationship studies on 3 culminated in the preparation of 4,5-bis(4-methoxyphenyl)-2-[(1-methylpiperazin-4-yl)carbonyl]thiaz ole (10a, FR122047) which exhibited potent inhibitory activity on MDA synthesis in vitro (IC50 = 0.088 microM) and platelet aggregation in guinea pigs ex vivo (100% inhibition even 6 h after 1.0 mg/kg administration) with vasodilatory activity in vitro (ED50 = 6.2 microM). Moreover, 10a demonstrated no ulcerogenesis effect in rats even at 100 mg/kg dosage (safety margin in rats is more than 70 while that of aspirin is only 1.2) in spite of its potent CO inhibition (IC50 = 0.43 microM14), while the use of aspirin, a CO inhibitor and the most popular thromboembolic drug, is restricted by the side effect. Pharmacokinetic studies on 10a have revealed that 10a is detectable in platelet-rich plasma but not in platelet-poor plasma 1 day after oral administration, which indicates that 10a tends to be localized in platelets. This property could be responsible for its low toxicity and reduction of side effects in clinical studies.
(-)-Delta9-Tetrahydrocannabinol ((-)-Delta9-THC) is the major active psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its derivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the neuronal cannabinoid receptor is found mostly in neuronal cells and tissues while CB2 or the peripheral cannabinoid receptor has been detected in spleen and in several cells of the immune system. It has previously been shown that activation of CB1 or CB2 receptors by cannabinoid agonists inhibits adenylyl cyclase activity. Utilizing Chinese hamster ovary cells and COS cells transfected with the cannabinoid receptors we report that (-)-Delta9-THC binds to both receptors with similar affinity. However, in contrast to its capacity to serve as an agonist for the CB1 receptor, (-)-Delta9-THC was only able to induce a very slight inhibition of adenylyl cyclase at the CB2 receptor. Morever, (-)-Delta9-THC antagonizes the agonist-induced inhibition of adenylyl cyclase mediated by CB2. Therefore, we conclude that (-)-Delta9-THC constitutes a weak antagonist for the CB2 receptor.
Two cannabinoid receptors have been identified to date; one is located predominantly in the central nervous system (CB1), whereas the other is located exclusively in the periphery (CB2). The purposes of this study were to explore further the binding requirements of the CB2 receptor and to search for compounds displaying distinct affinities for either cannabinoid receptor. The binding affinities of a series of cannabinoids tested previously at the CB1 receptor were determined at cloned human CB1 and CB2 receptors using a filtration assay. In addition, possible allosteric regulation of the CB2 receptor was examined. Sodium and a GTP analog elicited a concentration-dependent decrease in specific binding to the CB2 receptor. The affinity of cannabinol for CB2 receptors (Ki = 96.3 +/- 14 nM) was confirmed to be in approximately the same range as that of delta 9-THC (Ki = 36.4 +/- 10 nM). Affinities at cloned CB1 and CB2 receptors were compared with affinities determined in the brain. Although most of the chosen compounds did not discriminate between CB1 and CB2, several ligands were identified that showed selectivity. Affinity ratios demonstrated that two 2'-fluoro analogs of anandamide were over 23-fold selective for the CB1 receptor and confirmed the CB1 selectivity of SR141716A {N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamidehydrochloride}. In addition, WIN-55, 212-2 {(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl) methanone} and a closely related propyl indole analog were shown to be 6.75- and 27.5- fold selective, respectively, for the CB2 receptor. These ligands can now serve as a basis for the design of compounds with even greater selectivity.
A series of novel 1,5-diarylpyrazole derivatives was synthesized and tested for anti-inflammatory and analgesic activities to develop anti-inflammatory agents with fewer side effects than existing nonsteroidal anti-inflammatory drugs. The structure-activity relationships in this series were extensively studied. Electron-withdrawing substituents such as CN and CF3 were optimal at the 3-position of the pyrazole ring. Replacement of these substituents with bulky ones gave less active compounds. The 4-(methylsulfonyl)phenyl group seemed to be the optimal group at the 5-position of the pyrazole ring. The most potent compound was 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyrazole-3-carbonitrile (19a), with oral ED50 value of 0.030 and 0.47 mg/kg on adjuvant-induced arthritis and collagen-induced arthritis, respectively, and an ED30 value of 7.4 mg/kg in the yeast-induced hyperalgesia (Randall-Selitto) assay. Compound 19a also showed potent inducible cyclooxygenase (COX-2)-inhibitory activity (IC50 = 0.24 microM) with no COX-1 inhibition even at 100 microM.
Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.
A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.
Two subtypes of cannabinoid receptors are currently recognized, CB(1), found in brain and neuronal cells, and CB(2), found in spleen and immune cells. We have characterized 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) as a novel aryl pyrazole antagonist for the CB(1) receptor. CP-272871 competed for binding of the cannabinoid agonist (3)H-labeled (-)-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-4-[3-hydroxypropyl]cyclohexan-1-ol ([(3)H]CP-55940) at the CB(1) receptor in rat brain membranes with a K(d) value 20-fold greater than that of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). CP-272871 also competed for binding with the aminoalkylindole agonist (3)H-labeled (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone ([(3)H]WIN-55212-2), as well as the aryl pyrazole antagonist [(3)H]SR141716A. Inverse agonist as well as antagonist properties were observed for both SR141716A and CP-272871 in signal transduction assays in biological preparations in which the CB(1) receptor is endogenously expressed. SR141716A augmented secretin-stimulated cyclic AMP (cAMP) accumulation in intact N18TG2 neuroblastoma cells, and this response was reversed by the agonist desacetyllevonantradol. CP-272871 antagonized desacetyllevonantradol-mediated inhibition of adenylyl cyclase in N18TG2 membranes, and increased adenylyl cyclase activity in the absence of agonist. SR141716A and CP-272871 antagonized desacetyllevonantradol-stimulated (35)S-labeled guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding to brain membrane G-proteins, and decreased basal [(35)S]GTPgammaS binding to G-proteins. K(+) enhanced CP-272871 and SR141716A inverse agonist activity compared with Na(+) or NMDG(+) in the assay. These results demonstrated that the aryl pyrazoles SR141716A and CP-272871 behave as antagonists and as inverse agonists in G-protein-mediated signal transduction in preparations of endogenously expressed CB(1) receptors.
Review commissioned in 1996 by the Department of Health (DOH).
Assess therapeutic profile of cannabis and cannabinoids.
Medline search, references supplied by DOH and others, and personal communications.
Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.
An understanding of the actions of Cannabis (Marijuana) has evolved from folklore to science over the previous hundred years. This progression was spurred by the discovery of an endogenous cannabinoid system consisting of two receptors and two endogenous ligands. This system appears to be intricately involved in normal physiology, specifically in the control of movement, formation of memories and appetite control. As we are developing an increased understanding of the physiological role of endocannabinoids it is becoming clear that they may be involved in the pathology of several neurological diseases. Furthermore an array of potential therapeutic targets is being determined--including specific cannabinoid agonists and antagonists as well as compounds that interrupt the synthesis, uptake or metabolism of the endocannabinoids. This article reviews the recent progress in understanding the contribution of endocannabinoids to the pathology and therapy of Huntington's disease. Parkinson's disease, schizophrenia and tremor.
The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to activate CB(1) receptors, including CP55940, HU-210, and Delta(9)-tetrahydrocannabinol, failed to stimulate [(35)S]GTP gamma S binding in CB(1)(-/-) membranes. In CB(1)(-/-) membranes, SR141716A affected both basal and anandamide- or WIN55212-2-induced stimulation of [(35)S]GTP gamma S binding only at concentrations greater than 1 microM. In CB(1)(+/+) membranes, SR141716A inhibited only 84% of anandamide and 67% of WIN55212-2 stimulated [(35)S]GTP gamma S binding with an affinity appropriate for mediation by CB(1) receptors (K(B) approximately 0.5 nM). The remaining stimulation seemed to be inhibited with lower potency (IC(50) approximately 5 microM) similar to that seen in CB(1)(-/-) membranes or in the absence of agonist. Further experiments determined that the effects of anandamide and WIN55212-2 were not additive, but that the effect of mu opioid, adenosine A1, and cannabinoid ligands were additive. Finally, assays of different central nervous system (CNS) regions demonstrated significant activity of cannabinoids in CB(1)(-/-) membranes from brain stem, cortex, hippocampus, diencephalon, midbrain, and spinal cord, but not basal ganglia or cerebellum. Moreover, some of these same CNS regions also showed significant binding of [(3)H]WIN55212-2, but not [(3)H]CP55940. Thus anandamide and WIN55212-2 seemed to be active in CB(1)(-/-) mouse brain membranes via a common G protein-coupled receptor with a distinct CNS distribution, implying the existence of an unknown cannabinoid receptor subtype in brain.
Activation of peripheral cannabinoid CB(1) receptors elicits hypotension. Using the radioactive microsphere technique, we examined the effects of cannabinoids on systemic hemodynamics in anesthetized rats. The potent cannabinoid CB(1) receptor agonist HU-210 ([-]-11-OH-Delta(9) tetrahydrocannabinol dimethylheptyl, 10 microg/kg i.v.) reduced mean blood pressure by 57+/-5 mm Hg by decreasing cardiac index from 37+/-1 to 23+/-2 ml/min/100 g (P<0.05) without significantly affecting systemic vascular resistance index. HU-210 elicited a similar decrease in blood pressure following ganglionic blockade and vasopressin infusion. The endogenous cannabinoid anandamide (arachidonyl ethanolamide, 4 mg/kg i.v.) decreased blood pressure by 40+/-7 mm Hg by reducing systemic vascular resistance index from 3.3+/-0.1 to 2.3+/-0.1 mm Hg min/ml/100 g (P<0.05), leaving cardiac index and stroke volume index unchanged. HU-210, anandamide, and its metabolically stable analog, R-methanandamide, lowered vascular resistance primarily in the coronaries and the brain. These vasodilator effects remained unchanged when autoregulation was prevented by maintaining blood pressure through volume replacement, but were prevented by pretreatment with the cannabinoid CB(1) receptor antagonist SR141716A (N-[piperidin-1-yl]-5-[4-chlorophenyl]-1-[2,4-dichlorophenyl]-4-methyl-1H-pyrazole-3-carboxamide HCl; 3 mg/kg i.v.). Only anandamide and R-methanandamide were vasodilators in the mesentery. We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB(1) receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite. Differences between the hemodynamic profile of various cannabinoids may reflect quantitative differences in cannabinoid CB(1) receptor expression in different tissues and/or the involvement of as-yet-unidentified receptors.
There has been considerable debate about the reasons for the association observed between cannabis use and psychosis in both clinical and general population samples. Among the hypotheses proposed to explain the association are the following: 1) common factors explain the co-occurrence; 2 cannabis causes psychosis that would not have occurred in the absence of cannabis use; 3) cannabis precipitates psychosis among persons who were vulnerable to developing the disorders; 4) cannabis use worsens or prolongs psychosis among those who have already developed the disorder; and 5) that persons with psychosis are more likely to become regular or problematic cannabis users than persons without psychosis. This article evaluates the evidence on each of these hypotheses, including recent research on the role of the cannabinoid receptor system in schizophrenia. The evidence suggests that common factors do not explain the comorbidity between cannabis use and psychosis, and it is unlikely that cannabis use causes psychosis among persons who would otherwise not have developed the disorder. The evidence is more consistent with the hypotheses that cannabis use may precipitate psychosis among vulnerable individuals, increase the risk of relapse among those who have already developed the disorder, and may be more likely to lead to dependence in persons with schizophrenia.
The present study investigated the effect of the selective cannabinoid agonist, WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on body temperature. WIN 55212-2 (1, 2.5, 5, and 10 mg/kg, i.m.) induced hypothermia in a dose-dependent manner. The peak hypothermia occurred 60 to 180 min postinjection. Body temperature was still suppressed 5 h after the injection of the highest dose of WIN 55212-2. The selective CB(1) antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] (5 and 10 mg/kg, i.m.), blocked the WIN 55212-2-induced hypothermia, suggesting that CB(1) receptor activation mediated the hypothermia. In contrast, the selective CB(2) antagonist, SR144528 [N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide)] (5 mg/kg, i.m.), did not alter the WIN 55212-2-induced hypothermia. Neither SR141716A nor SR144528 alone altered body temperature. WIN 55212-2 (1-30 microg/microl) injected directly into the preoptic anterior hypothalamic nucleus (POAH) induced hypothermia in an immediate and dose-dependent fashion. The hypothermia produced by intra-POAH injection of WIN 55212-2 was brief, with body temperature returning to baseline 60 min postinjection. SR141716A (5 mg/kg, i.m.) abolished the hypothermia induced by intra-POAH injection of WIN 55212-2 (30 microg/microl), indicating that CB(1) receptors in the POAH mediated the hypothermia. The present results confirm the idea that CB(1) receptors mediate the hypothermic response to cannabinoid agonists. Moreover, the present data suggest that 1) the POAH is the central locus for thermoregulation, and 2) CB(1) receptors within the POAH are the primary mediators of cannabinoid-induced hypothermia.
Analogues of the biaryl pyrazole N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 5) were synthesized to investigate the structure-activity relationship (SAR) of the aminopiperidine region. The structural modifications include the substitution of alkyl hydrazines, amines, and hydroxyalkylamines of varying lengths for the aminopiperidinyl moiety. Proximity and steric requirements at the aminopiperidine region were probed by the synthesis of analogues that substitute alkyl hydrazines of increasing chain length and branching. The corresponding amide analogues were compared to the hydrazides to determine the effect of the second nitrogen on receptor binding affinity. The N-cyclohexyl amide 14 represents a direct methine for nitrogen substitution for 5, reducing the potential for heteroatom interaction, while the morpholino analogue 15 adds the potential for an additional heteroatom interaction. The series of hydroxyalkyl amides of increasing chain length was synthesized to investigate the existence of additional receptor hydrogen binding sites. In displacement assays using the cannabinoid agonist [(3)H](1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl) cyclohexan-1-ol (CP 55 940; 2) or the antagonist [(3)H]5, 14 exhibited the highest CB(1) affinity. In general, increasing the length and bulk of the substituent was associated with increased receptor affinity and efficacy (as measured in a guanosine 5'-triphosphate-gamma-[(35)S] assay). However, in most instances, receptor affinity and efficacy increases were no longer observed after a certain chain length was reached. A quantitative SAR study was carried out to characterize the pharmacophoric requirements of the aminopiperidine region. This model indicates that ligands that exceed 3 A in length would have reduced potency and affinity with respect to 5 and that substituents with a positive charge density in the aminopiperidine region would be predicted to possess increased pharmacological activity.
In superior cervical ganglion neurons, N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) competitively antagonizes the Ca(2+) current effect of the cannabinoid (CB) agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), and behaves as an inverse agonist by producing opposite current effects when applied alone. In contrast, in neurons expressing CB1 with a K-->A mutation at residue 3.28(192) (i.e., K3.28A), SR141716A competitively antagonizes the effects of WIN55212-2, but behaves as a neutral antagonist by producing no current effects itself. Receptor modeling studies suggested that in the CB1 inactive (R) state, SR1417A16A stabilizes transmembrane helix 6 in its inactive conformation via aromatic stacking with F3.36/W6.48. In this binding site, SR141716A would exhibit higher affinity for CB1 R due to a hydrogen bond between the SR141716A C3 substituent and K3.28(192), a residue available to SR141716A only in R. To test this hypothesis, a "mutant thermodynamic cycle" was constructed that combined the evaluation of SR141716A affinity at WT CB1 and K3.28A with an evaluation of the wild-type CB1 and K3.28A affinities of an SR141716A analog, 5-(4-chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole (VCHSR), that lacks hydrogen bonding potential at C3. Binding affinities suggested that K3.28 is involved in a strong interaction with SR141716A in WT CB1, but does not interact with VCHSR. Thermodynamic cycle calculations indicated that a direct interaction occurs between the C3 substituent of SR141716A and K3.28 in WT CB1. Consistent with these results, VCHSR acted as a neutral antagonist at WT CB1. These results support the hypothesis that hydrogen bonding of the SR141716A C3 substituent with K3.28 is responsible for its higher affinity for the inactive R state, leading to its inverse agonism.
Exploration of the central CB1 cannabinoid receptors using positron emission tomography (PET) will allow for an understanding of the pharmacological and physiological role played by these receptors in the CNS. Current tracers are highly lipophilic compounds that exhibit very high nonspecific to specific binding ratios and as a result are inapt for use in humans. We have synthesized a series of less lipophilic analogues of SR141716 to serve as potential radioligands. Binding affinities of the series and a functional electrophysiological assay of three of our compounds have been presented.
The major psychoactive constituent of Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial.
Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson’s disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of Δ9-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity.
Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB1 receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB1 receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment.
This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
The cannabinoid CB(1) receptor transmembrane helix (TMH) 3-4-5-6 region includes an aromatic microdomain comprised of residues F3.25, F3.36, W4.64, Y5.39, W5.43, and W6.48. In previous work, we have demonstrated that aromaticity at position 5.39 in CB(1) is crucial for proper function of CB(1). Modeling studies reported here suggest that in the inactive state of CB(1), the binding site of the CB(1) inverse agonist/antagonist SR141716A is within the TMH3-4-5-6 aromatic microdomain and involves direct aromatic stacking interactions with F3.36, Y5.39, and W5.43, as well as hydrogen bonding with K3.28. Further, modeling studies suggest that in the active state of CB(1), the CB agonist WIN55,212-2 binds in this same aromatic microdomain, with direct aromatic stacking interactions with F3.36, W5.43, and W6.48. In contrast, in the binding pocket model, the CB agonist anandamide binds in the TMH2-3-6-7 region in which hydrogen bonding and C-H.pi interactions appear to be important. Only one TMH3 aromatic residue, F3.25, was found to be part of the anandamide binding pocket. To probe the importance of the TMH3-4-5-6 aromatic microdomain to ligand binding, stable transfected cell lines were created for single-point mutations of each aromatic microdomain residue to alanine. Improper cellular expression of the W4.64A was observed and precluded further characterization of this mutation. The affinity of the cannabinoid agonist CP55,940 was unaffected by the F3.25A, F3.36A, W5.43A, or W6.48A mutations, making CP55,940 an appropriate choice as the radioligand for binding studies. The binding of SR141716A and WIN55,212-2 were found to be affected by the F3.36A, W5.43A, and W6.48A mutations, suggesting that these residues are part of the binding site for these two ligands. Only the F3.25A mutation was found to affect the binding of anandamide, suggesting a divergence in binding site regions for anandamide from WIN55,212-2, as well as SR141716A. Taken together, these results support modeling studies that identify the TMH3-4-5-6 aromatic microdomain as the binding region of SR141716A and WIN55,212-2, but not of anandamide.
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.
After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle Δ9-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest ‘additions’ to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids.
British Journal of Pharmacology (2004) 141, 765–774. doi:10.1038/sj.bjp.0705666
Diarylimidazolecarboxamides and diaryltriazolecarboxamides related to SR141716 were synthesized and tested for binding to the human CB(1) receptor. Suitably substituted imidazoles are comparably potent to the clinical candidate, whereas the analogous triazoles are less so due to the absence of an additional substituent on the azole ring.
Although P-glycoprotein (P-gp) is highly expressed in both intestinal epithelial cells and endothelial cells of brain capillaries, and functions as an efflux transporter in both organs, the impact of P-gp on intestinal absorption and brain uptake of drugs is quantitatively very different. The effect of P-gp on drug absorption is not quantitatively as important as suggested. Many drugs are good human P-gp substrates and yet exhibit reasonable oral bioavailability. In contrast, P-gp plays a quantitatively very important role in blocking the brain uptake of P-gp substrates. This review provides an overview of the role of P-gp in drug absorption and brain uptake, and explores possible factors that may explain the quantitative differences in the impact of P-gp on drug absorption and brain uptake.