Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes (original) (raw)
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Brain Research, 2014
Diazepam Rat a b s t r a c t Enormous progress in understanding the role of four populations of benzodiazepinesensitive GABA A receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABA A receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at α 1 -and α 5 -containing GABA A receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect watermaze performance. While lack of clear anxiolytic actions may be connected with an 0006-8993/$ -see front matter & (M.M. Savić).
Biological function of GABAA/benzodiazepine receptor heterogeneity
Journal of Psychiatric Research, 1995
,-Aminobutyric acid (GABA) is the most prominent of the inhibiting neurotransmitters in the brain. It exerts its main action through GABAA receptors. The receptors respond to the presence of GABA by the opening of an intrinsic anion channel. Hence, they belong to the molecular superfamily of ligand-gated ion channels. There exist in the brain multiple GABAA receptors that show differential distribution and developmental patterns. The receptors presumably form by the assembly of five proteins from at least three different subunits (~1-6,/31-3 and ;'1-3). The regulation of functional properties by benzodiazepine (BZ) receptor ligands, neurosteroids, GABA and its analogs differs dramatically with the ~ variant present in the complex. Additional variation of the GABAA receptors comes with the exchange of the 1' subunits. No clear picture exists for the role of the/~ subunits, though they may play an important part in the sensitivity of the channel receptor complex. The effects of BZ receptor ligands on animal behavior range from agonist effects, e.g. anxiolysis, sedation, and hypnosis, to inverse agonist effects, e.g. anxiety, alertness, and convulsions. The diversity of effects reflects the ubiquity of the GABAA/BZ receptors in the brain. Recent data provide some insight into the mechanism of action of BZ ligands, but no clear delineation can be drawn from a single ligand to a single behavioral effect. This may be due to the fact that intrinsic efficacies of the ligands differ between receptor subtypes, so that the diversity of native receptors is further complicated by the diversity of the mode the ligands act on GABAA receptor subtypes. The behavioral actions of alcohol (ethanol) are similar to those produced by GABAA receptor agonists. In agreement, alcohol-induced potentiation of GABAergic responses has often been observed at behavioral, electrophysiological and biochemical levels. Thus, there is clearly a GABAA-dependent component in the actions of alcohol. However, the site and mode of action of ethanol on GABAA BZ receptors remain controversial.
Neuropsychopharmacology, 2008
Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA A receptors containing a 1 , a 2 , a 3 or a 5 subunits. Genetic studies suggest that modulation at the a 1 subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA A receptors containing the a 1 subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for a 2 -, a 3 -, and a 5 -containing subtypes of GABA A receptors (SH-053-S-CH3 and SH-053-S-CH3-2 0 F) or essentially selective for a 5 subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of a 1 subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2 0 F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by a 5 -containing GABA A receptors. Hence, it could be of importance to avoid substantial agonist activity at a 5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.
A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model
International Journal of Medicinal Chemistry, 2015
An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume...
Psychopharmacology, 2010
Rationale-Experimental evidence suggests that the differential behavioral effects of benzodiazepines depend on their relative actions at γ-aminobutyric acid type A (GABA A) receptors that contain either an α1, α2, α3 or α5 subunit. Objectives-The present study was aimed at understanding the role of α3 subunit-containing GABA A (α3GABA A) receptors by examining the behavioral pharmacology of TP003 (4,2'difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridine-3-yl]biphenyl-2carbonitrile), which shows functional selectivity for α3GABA A receptors.
Tricyclic pyridones as functionally selective human GABAAα2/3 receptor-ion channel ligands
Bioorganic & Medicinal Chemistry Letters, 2004
A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the a 3 over the a 1 containing subtype of the human GABA A receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam. # 2004 Elsevier Ltd. All rights reserved.
The GABAA receptor and benzodiazepine acceptor site
SOJ Pharmacy & Pharmaceutical Sciences, 2018
The GABAA receptor is a member of the ion channel receptor family. It is sensitive to muscimol (agonist) as well as bicuculline and picrotoxin (antagonists). The binding of GABA on its recognition site causes the opening of a chlorine (Cl-) channel, which, allowing the Cl-ions to pass, produces the hyperpolarization of the target cell. The GABAA receptor is a transmembrane glycoprotein composed of 4 subunits, alpha, beta, gamma and delta, currently recognized. It is sensitive to muscimol (agonist) as well as bicuculline and picrotoxin (antagonists). There are several types of GABAA receivers, different from each other by some of their subunits. There are currently 6 subtypes of alpha subunits, 3 subtypes of beta subunits, 3 subtypes of gamma subunits and 1 subtype of delta subunits. This entails not only a great heterogeneity of structure but also a pharmacological heterogeneity, the consequences of which are still poorly understood. The GABAA receptor has, besides the GABA receptor sites, a variety of other topographically distinct receptor sites capable of recognizing pharmacologically active substances, such as benzodiazepines (BZDs)-barbiturates-neurosteroids-convulsants-alcohol. These substances act in an allosteric manner with the GABA receptor sites and modulate the GABAA response.