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Compound 4 modulates GABA-mediated currents in recombinant human GRCs.(a) Chemical structure of compound 4. (b) EC20 GABA-evoked currents recorded from HEK-293 cells expressing human 122L and 222L GABA receptors. GABA currents (I GABA) are shown in the absence (control) and presence of 1 M compound 4 (C4; n = 3−5 cells). (c) Histogram summary of the effects of compound 4 (1−30 M) on EC20 GABA-activated currents recorded from 122L () and 222L () GABA receptors. Inset shows 2 subunit−selective agent L-838,417, tested under conditions identical to those used for compound 4.
Source publication
Patients taking fluoroquinolone antibiotics such as norfloxacin exhibit a low incidence of convulsions and anxiety. These side effects probably result from antagonism of the neurotransmitter gamma-aminobutyric acid (GABA) at the brain GABA(A) receptor complex (GRC). Modification of norfloxacin yields molecules such as compound 4 that potentiate GAB...
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Citations
... Bioorg's animal experiments confirmed that the side groups of different quinolone drugs affected their GABA receptor affinity differently [23,24]. Some trials even attempted to modify the side group structure of norfloxacin to increase its affinity to GABA receptors so that such quinolone antibiotics could be used as new anxiolytics [25]. Moreover, the structure of the drug may be related to different main neurologic symptoms; for example, quinolone antibiotic neurotoxicity manifested more often as mental disorders, and carbapenem neurotoxicity manifested more often as convulsions. ...
Objective
End-stage kidney disease (ESKD) patients have a higher risk of antibiotic-associated encephalopathy (AAE) than other patients. We aimed to evaluate the prevalence, risk factors and outcomes of AAE in ESKD patients.
Method
A retrospective study of ESKD patients treated with intravenous antibiotics in our hospital from Jan. 1, 2006, to Dec. 31, 2015 was performed. AAE was diagnosed by the modified Delphi method. Control individuals were randomly selected from the remaining patients who did not exhibit neurologic symptoms. Logistic regression analysis was used to identify risk factors for AAE as well as the association between AAE and outcome.
Result
A total of 2104 patients were included in the study. The prevalence of AAE in our study was 4.4% (92/2104). The multivariate logistic regression analysis revealed that anuria (OR = 8.04, 95% CI: 4.13–15.65, p < 0.001), history of central nervous system disorder (OR = 3.03, 95% CI: 1.21–7.56, p = 0.018) and hypoalbuminemia (OR= 1.87, 95% CI: 1.01–3.47, p = 0.046) were independent factors associated with AAE in ESKD patients. After adjustment for confounders, AAE was associated with composite outcomes of in-hospital mortality and treatment withdrawal (OR = 4.36, 95% CI: 2.09–9.10, p < 0.001).
Conclusion
The prevalence of AAE was 4.4% in ESKD patients and varied among different antibiotics. Anuria, history of central nervous system disorder and hypoalbuminemia were associated with AAE in ESKD patients. AAE is associated with worse outcomes in ESKD patients.
... 1. Compound 4. The first compound claimed to be a2 selective was compound 4, a modified quinolone antibiotic that exhibited anxiolytic-like properties but did not cause sedation. It produced stronger effects than L-838,417 at a2-GABA A receptors but did not act via the benzodiazepine binding site (Johnstone et al., 2004). Unfortunately, however, only a1b2g2 and a2b2g2 receptors were investigated in this study, and to the best of our knowledge, no further information on this compound is available in the literature. ...
GABAA receptors are the major inhibitory transmitter receptors in the brain. They are ligand-gated chloride channels and the site of action of benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. GABAA receptors are composed of five subunits that can belong to different subunit classes. The existence of 19 homologous subunits and their distinct regional, cellular, and subcellular distribution gives rise to a large number of GABAA receptor subtypes with distinct pharmacology, which modulate different functions of the brain. A variety of compounds have been identified that were claimed to modulate selectively individual GABAA receptor subtypes. However, many of these compounds have only incompletely been investigated or, in addition to a preferential modulation of a receptor subtype, also modulate other subtypes at similar concentrations. Although their differential efficacy at distinct receptor subtypes reduced side effects in behavioral experiments in rodents, the exact receptor subtypes mediating their behavioral effects cannot be unequivocally delineated. In addition, the discrepant in vivo effects of some of these compounds in rodents and man raised doubts on the applicability of the concept of receptor subtype selectivity as a guide for the development of clinically useful drugs. Here, we provide an up-to-date review on the currently available GABAA receptor subtype-selective ligands. We present data on their actual activity at GABAA receptor subtypes, discuss the translational aspect of subtype-selective drugs, and make proposals for the future development of ligands with better anxioselectivity in humans. Finally, we discuss possible ways to strengthen the conclusions of behavioral studies with the currently available drugs.
... Ligands acting as partial agonists at the BZ-site of α2-and α3-containing GABA A Rs but not α1containing GABA A Rs exhibit anxiolytic-like activity in animals (Collins et al., 2002). It is the same for α2-containing GABA A selective dihydroquinoline (Johnstone et al., 2004). ...
... Given the proven efficacy of varenicline, a partial agonist of nAChR, it has been suggested that nAChR antagonists may aid smoking cessation [128]. Such drugs include mecamylamine (trade name Inversine), currently approved for the management of hypertension; lobeline, an alkaloid derived from the leaves of an Indian tobacco plant (Lobelia inflate) [73,129]; GTS-21, a derivative of anabaseine (a product in tobacco), which improves cognitive function and may be a possible novel treatment for dementia [130]; dianicline, a drug developed by Sanofi-Aventis, which has a pharmacological profile similar to that of varenicline; sazetidine, which is specified for the treatment of anxiety and depression; UCI-30002, a negative allosteric modulator of nAChR and an agonist of gamma-aminobutyric acid (GABA) receptors [131]; and AT-1001 [N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1] nonan-3-amine], a high-affinity and highly selective ligand at the nAChR [132]. ...
A wide range of support is available to help smokers to quit and to aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications with (1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and (2) 24 alternative products: cytisine (novel outside Central and Eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective serotonin reuptake inhibitors, supplements (e.g. St John's wort), silver acetate, Nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOIs), opioid antagonists, nicotinic acetylcholine receptor (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate (NMDA) receptors, dopamine agonists (e.g. levodopa), pioglitazone (Actos; OMS405), noradrenaline reuptake inhibitors and the weight management drug lorcaserin. Six 'ESCUSE' criteria-relative efficacy, relative safety, relative cost, relative use (overall impact of effective medication use), relative scope (ability to serve new groups of patients) and relative ease of use-are used. Many of these products are in the early stages of clinical trials; however, cytisine looks most promising in having established efficacy and safety with low cost. Electronic cigarettes have become very popular, appear to be efficacious and are safer than smoking, but issues of continued dependence and possible harms need to be considered.
... Approximately 0.1 g (brain) was combined with 1 mL phosphatebuffered saline (pH 7.4) and homogenized with a Tissue-Tearor (Biospec Products, Bartlesville, OK, USA). Homogenized brain samples (100 µL) were combined with 1-029 (Johnstone et al., 2004) (1 µL) as internal standard. Brain samples were extracted with 0.5 mL ethyl acetate (EtOAc) and vortexed for 30 s. Plasma samples (100 µL) were combined with 1 µL 1-029 (10 µg/mL) and extracted with 0.5 mL acetonitrile (ACN) and vortexed for 30 s. Brain and plasma extract/solvent mixtures were spun 1000 × g for 10 min. ...
... The parent/daughter transition mass (391.1 > 140.5) was detected at 10.8 min at a 0.3mL/min rate of infusion using a cone voltage of 20 V, collision energy of 40 eV, dwell of 0.1 s, 3.0 kV capillary voltage, 5 V extractor, source temperature of 120°C, desolvation temperature 300°C, and collision gas flow of 0.46 mL/min. Compound 1-029 (Johnstone et al., 2004) was used as an internal standard. ...
GABAergic anxiolytics have well-documented centrally mediated side effects including sedation, potentiation of ethanol, tolerance, abuse liability and memory impairment. Most research directed towards identifying an anxioselective GABAergic therapeutic has been based upon the theory that these side effects could be mitigated by avoiding α1/5-subunit GABAA receptors while specifically targeting those with the α2/3-subunit. Unfortunately, there are prominent exceptions to this theory and it has yet to be translated into clinical success. We previously demonstrated that β2/3-subunit-selective GABAA receptor-positive allosteric modulators act as anxiolytics with reduced sedation and ethanol potentiation regardless of their activity at α1-subunit GABAA receptors. The prototypical β2/3-subunit-selective positive allosteric modulator, 2-261, is further characterized here for additional side effects commonly associated with central GABAA receptor activation. In mice, 10 times the anxiolytic dose (10 mg/kg) of 2-261 does not induce behavioral tolerance in the elevated plus maze following a 2 week subchronic treatment. In rats, an anxiolytic dose (10 mg/kg) of 2-261 is inactive in conditioned place preference, suggesting a reduced abuse liability. In rats, 10 times the anxiolytic dose (100 mg/kg) of 2-261 does not have a significant amnestic effect in the radial arm maze, suggesting a greater therapeutic index for memory impairment. These results suggest that β2/3-subunit subtype-selective GABAA receptor-positive allosteric modulators not only have reduced sedative liability, but also a reduction in other central side effects commonly associated with broader GABAA receptor activation. β2/3-subunit-selective compounds may represent a novel design template for anxiolytics with benzodiazepine-like efficacy and mitigated side effects.
... Such anxiety effects have been reported with ciprofloxacin, norfloxacin, gatifloxacin, sparfloxacin and levofloxacin in experimental animals. The anxiogenic effect could well be related to inhibition of GABA A receptor complex (Johnstone et al., 2004). Quinolones have an inhibitory effect on the receptor binding of GABA A , and may thus exert an inhibitory CNS stimulant action (Akahane et al., 1994). ...
... More recently, however, an anxiolytic effect has been reported by modifying norfloxacin. The anxiogenic effect could well be related to inhibition of GABA A receptor complex (Johnstone et al., 2004). The role of gamma-aminobutyric acid (GABA) in anxiety is well documented (Sen et al., 2007). ...
Prulifloxacin, the prodrug of ulifloxacin, is a broad spectrum oral fluoroquinolones antibacterial agent. Fluoroquinolones have been used for the treatment of bacterial infection for many years. Although they were considered as relatively safe drugs, various adverse effects have recently been reported along with increase in the usage of new generation fluoroquinolones. In the present study, prulifloxacin 200 and 400 mg/kg were screened on anxiety parameter in mice. Our result suggested that prulifloxacin (200 and 400 mg/kg) exerted anxiety-like effect in the elevated plus maze, hole board apparatus and light/dark exploration test in mice.
... In view of the limitations of current therapies, one avenue of pharmacological research has focused on developing novel "anxioselectives," drugs capable of producing a rapid and robust anxiolysis associated with BZs, but with a reduced potential for sedation and related side effects [5,6,[19][20][21][22][23][24]. A number of compounds have been identified that act through the GABA A receptors targeted by BZs, and exhibit subtype selectivity and/or lower efficacy than "classical" 1,4-benzodiazepines (e.g., diazepam) to augment GABA stimulated chloride currents [5,6]. ...
Preclinical studies demonstrated that ocinaplon, a positive allosteric modulator of GABA(A) receptors, possesses anxiolytic-like actions at doses devoid of the side effects typically associated with benzodiazepines. The aim of this study was to evaluate the effects of ocinaplon in a multicenter, double-blind proof-of-concept trial of male and female outpatients who met DSM-IV criteria for GAD with no coexisting depression, and had a baseline score of > or =20 on the Hamilton Scale for Anxiety (HAM-A). Patients with <20% reduction in HAM-A to placebo in a single-blind 7-day run-in period were randomly assigned to treatment with ocinaplon 90 mg t.i.d. (n = 31) or placebo for 28 days (n = 29). Ocinaplon was more effective than placebo in reducing HAM-A scores (P= 0.009). Patients assigned to ocinaplon exhibited a mean improvement of 14.2 points (SE = 2.6) on the total score of the HAM-A scale at the conclusion of the trial, while patients assigned to placebo obtained a mean improvement of 6.3 points (SE = 2.0). A significant (P= 0.023) difference in improvement between ocinaplon and placebo was observed beginning at and continuing from 1-week after the initiation of dosing. The proportion of patients with treatment-emergent adverse events (TEAE) was not statistically significant between ocinaplon and placebo. One serious adverse event (SAE) occurred in the ocinaplon group that was considered possibly related to study medication (icterus following transaminase elevations). The patient had preexisting medical conditions that may have contributed to this SAE. A full recovery was observed with no residual effects. The overall safety profile revealed no patterns of TEAEs, including those effects typically associated with other anxiolytic and/or benzodiazepine compounds, such as sedation. Ocinaplon appears to be a well-tolerated and effective treatment for GAD. It produces a rapid onset of anxiolytic action absent the side effects (e.g., dizziness, sedation) typically reported following anxiolytic doses of benzodiazepines.
... Another novel antagonist currently being examined for potential use as a smoking cessation therapeutic is UCI-30002 [221]. UCI-30002 is a positive allosteric modulator of GABA A receptors [222]; however, since GABA A and nAChRs are both members of the ligand-gated ion channel superfamily, it was hypothesized that this novel compound may have efficacy as an allosteric modulator at α4β2* nAChRs [221]. UCI-30002 inhibited nicotine-evoked currents in Xenopus oocytes expressing neuronal α4β2, α7 and α3β4 nAChR subtypes [221]. ...
Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors.
... To develop alternative drugs with minimal side effects, there is a need for new GABA A receptor BZ site ligands with a selective activity profile. Consequently, a list of compounds structurally different from the BZ nucleus have been identified as BZ site ligands, such as b-carboline (Braestrup et al., 1984), triazelopyridazines, quinolines (Gardner et al., 1993;Johnstone et al., 2004), and flavonoids (Marder and Paladini, 2002;Wang et al., 2005). Baicalin, a natural flavonoid, was previously identified as a BZ site ligand using radioligand binding assays (Hui et al., 2000) and was suggested to elicit an anxiolytic-like effect through GABA A receptors without sedative and myorelaxant side effects by mice behavioral tests (Liao et al., 2003;Xu et al., 2006). ...
Baicalin, a naturally occurring flavonoid, was previously reported to induce anxiolytic-like effect devoid of sedation and myorelaxation in mice, acting through type A gamma-aminobutyric acid (GABA(A)) receptor benzodiazepine (BZ) site. The present study further expanded the behavioral pharmacology profile of baicalin and subtype selectivity was explored as a possible mechanism underlying its in vivo effects on mice. Baicalin was characterized using convulsion, memory, and motor function related animal tests; and its selectivity towards recombinant GABA(A) receptor subtypes expressed in HEK 293T cells was determined by radioligand binding assay and electrophysiological studies. In the picrotoxin-induced seizure, step-through passive avoidance and rotarod tests, the anticonvulsant, amnesic and motor incoordination effects commonly associated with classical BZs were not observed when baicalin was administered at effective anxiolytic doses, demonstrating a separation of the anticonvulsant, amnesic and motor incoordination effects from the anxiolytic-like effect. Although baicalin exhibited higher binding affinity for the alpha1-containing GABA(A) subtype compared with alpha2-, alpha3-, and alpha5-containing subtypes, this was not statistically significant. In contrast to the classical BZ diazepam, baicalin showed significant preference for alpha2- and alpha3-containing subtypes compared to alpha1- and alpha5-containing subtypes in whole-cell patch clamp studies (P < 0.01). Its subtype selectivity suggested that baicalin exerted its in vivo anxiolytic-like effect mainly through the alpha2- and alpha3-containing subtypes. Therefore, the present study revealed an underlying mechanism for the selective anxiolytic profile of baicalin, suggesting alpha2- and alpha3-containing subtypes were important drug targets for flavonoid-based anxiolytics.
... Our laboratory has previously identified a series of positive allosteric modulators of GABA A receptors (Johnstone et al., 2004). Using the rationale that allosteric sites may be conserved between GABA A receptors and nAChRs because they belong to the same superfamily of ligand-gated ion channels, we screened our library of allosteric modulators at ␣42 nAChRs in search of negative efficacy modulators. ...
Drugs that antagonize nicotinic acetylcholine receptors (nAChRs) can be used to inhibit nicotine-induced behavior in both humans and animals. The aim of our experiments is to establish a proof-of-principle that antagonism of nAChRs by negative allosteric modulation can alter behavior in a relevant animal model of addiction, nicotine self-administration. We have identified a novel, negative allosteric modulator of nAChRs, UCI-30002 [N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline], with selectivity for the major neuronal nAChR subtypes over muscle-type nAChRs. After systemic administration, UCI-30002 significantly reduces nicotine self-administration in rats on both fixed ratio and progressive ratio schedules of reinforcement. The minimum effective dose that significantly alters nicotine self-administration corresponds to brain concentrations of UCI-30002 that produce at least 30% inhibition of the major neuronal nAChR subtypes measured in vitro. UCI-30002 has no effect on responding for food reinforcement in rats on either type of schedule, indicating that there is no effect on general responding or natural reward. UCI-30002 represents validation of the concept that negative allosteric modulators may have significant benefits as a strategy for treating nicotine addiction and encourages the development of subtype-selective modulators.
