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![A: chemical structure of tacrine (9-amino-1,2,3,4-tetrahydroacri- dine). B: bis(7)-tetrahydroaminacrine [bis(7)-tacrine].](profile/Carles-Solsona/publication/11908394/figure/fig2/AS:349290493956102@1460288751440/A-chemical-structure-of-tacrine-9-amino-1-2-3-4-tetrahydroacri-dine-B.png)
A: chemical structure of tacrine (9-amino-1,2,3,4-tetrahydroacri- dine). B: bis(7)-tetrahydroaminacrine [bis(7)-tacrine].
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Bis(7)-tacrine is a potent acetylcholinesterase inhibitor in which two tacrine molecules are linked by a heptylene chain. We tested the effects of bis(7)-tacrine on the spontaneous synaptic activity. Miniature endplate potentials (MEPPs) were recorded extracellularly on slices of electric organ of Torpedo marmorata. Bis(7)-tacrine, at a concentrati...
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... the early 1990s, a number of second-generation AChE inhibitors were developed, some of them based on the chemical structure of the tacrine molecule. Bis(7)-tetrahydroaminacrine [bis(7)-tacrine; Fig. 1] is a potent and selective inhibitor of AChE, in which two tacrine molecules are linked by a hepty- lene chain spaced so as to permit simultaneous binding at the catalytic and peripheral sites of AChE ( Pang et al. 1996). Bis(7)-tacrine is up to 150-fold more potent and 250-fold more selective in inhibiting AChE than tacrine over ...
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To identify the molecular determinants underlying the pharmacological diversity of neuronal nicotinic acetylcholine receptors, we compared the alpha7 homo-oligomeric and alpha4beta2 hetero-oligomeric receptors. Sets of residues from the regions initially identified within the agonist binding site of the alpha4 subunit were introduced into the alpha...
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When the four subunits of the Torpedo californica nicotinic acetylcholine receptor (AChR) are expressed in mammalian fibroblasts, they properly assembly into alpha 2 beta gamma delta pentamers only at temperatures lower than 37 degrees C (Claudio, T., W. N. Green, D. S. Hartman, D. Hayden, H. L. Paulson, F. J. Sigworth, S. M. Sine, and A. Swedlund....
Assembly of ionotropic neurotransmitter receptors typified by acetylcholine receptors (AChRs) is thought to be directed by an N-terminal extracellular domain of a subunit. Consistent with this hypothesis, chimeras with the delta subunit N-terminal domain fused to the rest of the gamma subunit can substitute for delta, but not gamma, subunits during...
The rotational diffusion of the acetylcholine (ACh) receptor in subsynaptic membrane fragments from Torpedo marmorata electric organ was investigated with a spin-labelled alpha-bungarotoxin. A toxin with two spin labels was first synthesized; the conventional electron spin resonance spectrum (e.s.r.) of this toxin bound to the receptor indicated: (...
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Citations
... Cholinesterase inhibitors which pass the blood-brain barrier have been used for symptomatic treatment in some brain neurodegenerative diseases. However, some AChE inhibitors, such as physostigmine [21,22], bis(7)-tacrine [23], BW284c51 [24], and natural alkylpyridinium salts and their synthetic analogs [25][26][27] can have dual effects on the cholinergic system. Besides inhibiting AChE, they can interact with muscle-type nicotinic acetylcholine receptors (nAChRs) in a concentration-dependent manner, and disrupt the neuromuscular transmission. ...
In addition to antibacterial and antitumor effects, synthetic ruthenium complexes have been reported to inhibit several medicinally important enzymes, including acetylcholinesterase (AChE). They may also interact with muscle-type nicotinic acetylcholine receptors (nAChRs) and thus affect the neuromuscular transmission and muscle function. In the present study, the effects of the organometallic ruthenium complex of 5-nitro-1,10-phenanthroline (nitrophen) were evaluated on these systems. The organoruthenium-nitrophen complex [(η6-p-cymene)Ru(nitrophen)Cl]Cl; C22H21Cl2N3O2 Ru (C1-Cl) was synthesized, structurally characterized and evaluated in vitro for its inhibitory activity against electric eel acetylcholinesterase (eeAChE), human recombinant acetylcholinesterase (hrAChE), horse serum butyrylcholinesterase (hsBChE) and horse liver glutathione-S-transferase. The physiological effects of C1-Cl were then studied on isolated mouse phrenic nerve-hemi-diaphragm muscle preparations, by means of single twitch measurements and electrophysiological recordings. The compound C1-Cl acted as a competitive inhibitor of eeAChE, hrAChE and hsBChE with concentrations producing 50 % inhibition (IC50) of enzyme activity ranging from 16 to 26 μM. Moreover, C1-Cl inhibited the nerve-evoked isometric muscle contraction (IC50 = 19.44 μM), without affecting the directly-evoked muscle single twitch up to 40 μM. The blocking effect of C1-Cl was rapid and almost completely reversed by neos-tigmine, a reversible cholinesterase inhibitor. The endplate potentials were also inhibited by C1-Cl in a concentration dependent manner (IC 50 = 7.6 μM) without any significant change in the resting membrane potential of muscle fibers up to 40 μM. Finally, C1-Cl (5-40 μM) decreased (i) the amplitude of miniature endplate potentials until a complete block by concentrations higher than 25 μM and (ii) their frequency at 10 μM or higher concentrations. The compound C1-Cl reversibly blocked the neuromuscular transmission in vitro by a non-de-polarizing mechanism and mainly through an action on postsynaptic nAChRs. The compound C1-Cl may be therefore interesting for further preclinical testing as a new competitive neuromuscular blocking, and thus myorelaxant, drug.
... Bis(7)-tacrine has a broad and complex pharmacological profile. Besides highly selective inhibition potency towards AChE, it emerged as a potent inhibitor of other enzymes like β-secretase 1 (BACE-1), nitric-oxide synthase and receptors including NMDA, serotonin 5-HT 3 , gamma-aminobutyric acid GABA A , nicotinic and others, all of them being involved in the pathophysiology of neurodegenerative disorders [23,[34][35][36]. Bis(7)-tacrine is able to inhibit self-aggregation and also AChE-induced aggregation of Aβ protein [37]. ...
Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.
... Three studies included both in vitro and in vivo approaches. The molecular target that was primarily studied was AChE in 11 studies (Li et al., 1999;Wang et al., 1999b;Ros et al., 2001;Hu et al., 2002Hu et al., , 2015bFu et al., 2006;Yu et al., 2008;Pan et al., 2009;Bolognesi et al., 2010;Rizzo et al., 2011;Qian et al., 2014), followed by the NMDA receptor (n = 8) (Baifang et al., 2001;Li et al., 2005Li et al., , 2007bLuo et al., 2007;Liu et al., 2008a,b;Zhang et al., 2011;Liu and Li, 2012). The BChE was under scrutiny in five studies (Wang et al., 1999b;Hu et al., 2002;Bolognesi et al., 2010;Rizzo et al., 2011;Qian et al., 2014), the BACE-1 in four studies (Fu et al., 2008(Fu et al., , 2009Bolognesi et al., 2010;Rizzo et al., 2011), the GABA receptor in three studies (Li et al., 1999(Li et al., , 2007aZhou et al., 2009), the nitric oxide synthase (NOS) in two studies (Li et al., , 2007b, the Kv4.2 potassium channels also in two studies (Nie et al., 2007;Li et al., 2010), the serotonin receptor 5-HT 3 in one study (Luo et al., 2004), the α-secretase also in one study (Fu et al., 2009), the L-type voltagedependent Ca 2+ channels in one study , and the choline acetyl transferase in one study as well (Liu et al., 2000). ...
... Although the pathological processes in AD are not wellunderstood, it is clear that disturbances in the cholinergic system and other neurotransmitters play a pivotal role in the pathogenesis of this neurodegenerative disorder (Han et al., 2012). Strategies to develop drugs for AD have focused on acetylcholinesterase (AChE) as a target for drug design based on the cholinergic hypothesis for AD (Ros et al., 2001;Lopes et al., 2017). The cholinergic hypothesis states that increased levels of acetylcholine in the brain alleviate the cognitive deficiencies observed in AD (Ros et al., 2001). ...
... Strategies to develop drugs for AD have focused on acetylcholinesterase (AChE) as a target for drug design based on the cholinergic hypothesis for AD (Ros et al., 2001;Lopes et al., 2017). The cholinergic hypothesis states that increased levels of acetylcholine in the brain alleviate the cognitive deficiencies observed in AD (Ros et al., 2001). Although a series of AChE inhibitors have been extensively studied, none of them represent a real cure for AD (Ros et al., 2001;Lopes et al., 2017). ...
Background: The exact mechanisms involved in the pathogenesis of neurodegenerative conditions are not fully known. The design of drugs that act on multiple targets represents a promising approach that should be explored for more effective clinical options for neurodegenerative disorders. B7C is s synthetic drug that has been studied for over 20 years and represents a promising multi-target drug for the treatment of neurodegenerative disorders, such as AD.
Aims: The present systematic review, thus, aims at examining existing studies on the effect of B7C on different molecular targets and at discussing the relevance of B7C in neurological disorders.
Methods: A list of predefined search terms was used to retrieve relevant articles from the databases of Embase, Pubmed, Scopus, and Web of Science. The selection of articles was done by two independent authors, who were considering articles concerned primarily with the evaluation of the effect of B7C on neurological disorders. Only full-text articles written in English were included; whereas, systematic reviews, meta-analyses, book chapters, conference subtracts, and computational studies were excluded.
Results: A total of 2,266 articles were retrieved out of which 41 articles were included in the present systematic review. The effect of B7C on molecular targets, including AChE, BChE, BACE-1, NMDA receptor, GABA receptor, NOS, and Kv4.2 potassium channels was evaluated. Moreover, the studies that were included assessed the effect of B7C on biological processes, such as apoptosis, neuritogenesis, and amyloid beta aggregation. The animal studies examined in the review focused on the effect of B7C on cognition and memory.
Conclusions: The beneficial effects observed on different molecular targets and biological processes relevant to neurological conditions confirm that B7C is a promising multi-target drug with the potential to treat neurological disorders.
... In this way the oocytes acquired native nAChRs, which were already synthesised and fully assembled in the electric organ of Torpedo. The oocytes could subsequently be used to evaluate the physiological and pharmacological properties of native Torpedo nAChRs [37][38][39][40] using the standard two-electrode voltage-clamp technique [41]. ...
It is important in drug discovery to demonstrate that activity of novel drugs found by screening on recombinant receptors translates to activity on native human receptors in brain areas affected by disease. In this review, we summarise the development and use of the microtransplantation technique. Native receptors are reconstituted from human brain tissues into oocytes from the frog Xenopus laevis where they can be functionally assessed. Oocytes microtransplanted with hippocampal tissue from an epileptic patient were used to demonstrate that new antiepileptic agents act on receptors in diseased tissue. Furthermore, frozen post-mortem human tissues were used to show that drugs are active on receptors in brain areas associated with a disease; but not in areas associated with side effects.
... (40) Dalším zjištěným mechanismem účinku bylo, že takrin stejně jako bis(7)-takrin ovlivňují spontánní synaptickou aktivitu nikotinových receptorů. (42) Obdobný trend v afinitě na daný cíl, který byl pozorován u GABA A receptorů lze vypozorovat i v tomto případě, kdy bis(7)-takrin vykázal 100×-1000× vyšší afinitu k tomuto receptoru oproti takrinu. Zajímavostí je, že přesný mechanismus se u obou derivátů lišil. ...
... Inhibition of acetylcholinesterase by bis(7) tacrine is 1000 times more than tacrine, moreover its special structure enables simultaneous inhibition of the active and peripheral anionic sites. Furthermore, bis(7)tacrine has beneficial interactions with the β-secretase enzyme and NMDA and GABA A receptors (Li et al., 2009; Minarini et al., 2012; Y. Pang, 2001; Rydberg et al., 2006; Shu et al., 2012) In 2012, Minarini et al. introduced a new compound called cystamine-tacrine dimer. Their experimental studies have shown that cystamine-tacrine dimer has lower toxicity than bis(7) tacrine. ...
The infamous chronic neurodegenerative disease, Alzheimer's, that starts with short term memory loss and eventually leads to gradual bodily function decline which has been attributed to the deficiency in brain neurotransmitters, acetylcholine and butylcholine. As a matter of fact, design of compounds that can inhibit cholinesterases activities (acetylcholinesterase (AChE) and butylcholinesterase (BChE)) has been introduced as an efficient method to treat Alzheimer's. Among proposed compounds, bis(7)tacrine (B7T) is recognized as a noteworthy suppressor for Alzheimer's disease. Recently a new analogue of bis(7)tacrine, cystamine-tacrine dimer is offered as an agent to detain Alzheimer's complications, even better than the parent compound. In this study, classical molecular dynamic simulations has been employed to take a closer look into the modes of interactions between the mentioned ligands and both cholinesterase enzymes. According to our obtained results, the structural differences in the target enzymes active sites result in different modes of interactions and inhibition potencies of the ligands against both enzymes. The obtained information can help to investigate those favorable fragments in the studied ligands skeletons that have risen potency of the analogue in comparison to the parent compound to design more potent multi target ligands to heal Alzheimer's disease.
... Based on the structure and anti-AChE activities of APS12-2 and APS3 (both are quaternary ammonium compounds), effects on neuro-muscular transmission were expected. sAPS are structurally related to quaternary ammonium compounds, like physostigmine, bis(7)-tacrine and BW284c51, some of which have dual effects and, in a concentration-dependent manner, inhibit either AChE or nicotinic acetylcholine receptors (nAChR) [50][51][52][53]. The effects on neuro-muscular transmission were revealed by experiments with both analogues on neuromuscular preparation [42,49]. ...
Polymeric 3-alkylpyridinium salts (poly-APS) are among the most studied natural bioactive compounds extracted from the marine sponge, Reniera sarai. They exhibit a wide range of biological activities, and the most prominent among them are the anti-acetylcholinesterase and membrane-damaging activity. Due to their membrane activity, sAPS can induce the lysis of various cells and cell lines and inhibit the growth of bacteria and fungi. Because of their bioactivity, poly-APS are possible candidates for use in the fields of medicine, pharmacy and industry. Due to the small amounts of naturally occurring poly-APS, methods for the synthesis of analogues have been developed. They differ in chemical properties, such as the degree of polymerization, the length of the alkyl chains (from three to 12 carbon atoms) and in the counter ions present in their structures. Such structurally defined analogues with different chemical properties and degrees of polymerization possess different levels of biological activity. We review the current knowledge of the biological activity and toxicity of synthetic poly-APS analogues, with particular emphasis on the mechanisms of their physiological and pharmacological effects and, in particular, the mechanisms of toxicity of two analogues, APS12-2 and APS3, in vivo and in vitro.
... Bis(7)tacrine greatly increases the spontaneous quantal release from peripheral cholinergic terminals in the electric organ of Torpedo marmorata, at lower concentrations than tacrine. Moreover, it also blocks AChinduced currents of Torpedo electric organ [183]. Bis (7)tacrine was demonstrated to inhibit the serotonin 3 receptor subtype (5-HT 3 R) mediated current on rat trigeminal ganglion (TG) neurons in a competitive manner [184]. ...
Alzheimer`s disease (AD) is a multifactorial neurodegenerative disorder with several target proteins contributing to its aetiology. Pathological, genetic, biochemical, and modeling studies all point to a critical role of Aβ aggregation in AD. Though there are still many enigmatic aspects of the Aβ cascade, none of the gaps invalidate the hypothesis. The amyloid hypothesis determines that the production, aggregation and accumulation of Aβ in the brain gives rise to a cascade of neurotoxic events that proceed to neuronal degeneration. Different targets of the disease include APP pathogenic cleavage, cytoskeletal destabilization, neurotransmitter and ion dyshomeostasis, metal ion accumulation, protein misfolding, oxidative stress, neuronal death and gene mutations. Thus, disease-modifying treatments for AD must interfere with the pathogenic steps responsible for the clinical symptoms: the deposition of extracellular Aβ plaques, the intracellular neurofibrillary tangles, inflammation, oxidative stress, iron deregulation, among others. The observations supporting the development of multifunctional compounds in association with the perception that several dual binding site AChEIs were able to reach different targets guided the development of a new drug design strategy, the multi-target-directed-ligand (MTDL) approach. This may be regarded as the buildup of hybrid molecules composed of distinct pharmacophores of different drugs. Thus, each pharmacophore of the new hybrid drug would preserve the capacity of interacting with their specific sites on the targets and, therefore, generate multiple specific pharmacological responses which would enable the treatment of multi-factorial diseases. This review summarizes a few current therapeutic trends on MTDL strategy intended to halt or revert the progression of the disease.
... It also had some effect on nAChRs. 124 Bis(7)-tacrine revealed a NMDAR antagonist character, with an IC 50 of 0.76 mM preventing glutamate-induced neuronal apoptosis. 125 Interestingly, a few years later a regulatory effect of L-type calcium channels was reported; 126 such an effect has several neuroprotective implications discussed in following paragraphs. ...
With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one-compound-one-target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium-permeable channels such as voltage-dependent calcium channels, N-methyl-D-aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one-compound-various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD. © 2011 Wiley Periodicals, Inc. Med Res Rev.
... Another AChE inhibitor, bis(7)-tacrine, also reversibly inhibits Torpedo nAChRs (IC 50 = 0.162 μM). The inhibition is not voltage- dependent, and bis(7)-tacrine enhances desensitization of nAChRs ( Ros et al., 2001). Also the selective AChE inhibitor BW284c51 blocks ACh-activating current in Torpedo nAChRs (IC 50 = 0.2-0.5 μM), and enhances receptor desensitization (Olivera-Bravo et al., 2005). ...
APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC(50)=0.74μM), without affecting directly-elicited twitch tension up to 2.72μM. The compound (0.007-3.40μM) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68μM, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC(50)=0.36μM) without significant change in the resting membrane potential of the muscle fibers up to 3.40μM. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (α1(2)β1γδ) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC(50)=0.0005μM), indicating a higher affinity of the compound for Torpedo (α1(2)β1γδ) than for the mouse (α1(2)β1γε) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction.
