GABAC Receptors as Drug Targets

Johnston, Graham A.R.; Chebib, Mary; Hanrahan, Jane R.; Mewett, Kenneth N.

doi:10.2174/1568007033482805

Cited by 80 publications

(69 citation statements)

References 84 publications

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“…To date, 16 different GABA A subunit isoforms have been identified (excluding the GABA C receptor subunits ρ1-ρ3), and a large number of functional hetero pentamers have been described. [3][4][5] Several studies with animal models have revealed distinct pharmacological effects that are specifically mediated by different receptor isoforms. 6 These findings have spurred a race for the development of novel ion channel modulators showing specificity restricted to distinct isoforms and thus, it is hoped, circumventing well-known side effects of current GABA A R drugs, such as sedation, ataxia, cognitive impairment, amnesia, and potential for abuse.…”

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confidence: 99%

Use of FLIPR Membrane Potential Dyes for Validation of High-Throughput Screening with the FLIPR and μARCS Technologies: Identification of Ion Channel Modulators Acting on the GABAA Receptor

Joesch¹,

Guevarra²,

Parel³

et al. 2008

SLAS Discovery

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Fluorometric imaging plate reader (FLIPR) membrane potential dyes (FMP-Red-Dye and FMP-Blue-Dye) were evaluated for the detection of compounds acting either as positive allosteric modulators or agonists on the GABA A receptor (GABA A R). A stable HEK293 cell line with constitutive expression of the rat GABA A R α1, β2, and γ2 genes was used to establish a functional high-throughput screening (HTS) assay based on measurement of the membrane potential change in living cells. The assay was validated with the FLIPR technology for identification of agonists and positive allosteric modulators using GABA and diazepam as model compounds. The FMP-Red-Dye showed better performance than the FMP-Blue-Dye, and the effects induced by GABA and diazepam were comparable to electrophysiology data. Subsequently, the assay was also validated with an ultra-HTS approach known as microarrayed compound screening (μARCS). The LOPAC library was used in a test screen for an initial assessment of the technology. Finally, the FLIPR and μARCS technologies were tested with a larger screening campaign. A focused library of 3520 putative positive modulators was tested with the FLIPR assay, and a diverse subset of 84,480 compounds was selected for screening with the μARCS technology. All hits were subjected to verification using the FLIPR technology, and confirmed hits were subsequently evaluated by EC50 determination. Finally, selected hits were further confirmed with electrophysiology testing. (Journal of Biomolecular Screening 2008:218-228)

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confidence: 99%

Use of FLIPR Membrane Potential Dyes for Validation of High-Throughput Screening with the FLIPR and μARCS Technologies: Identification of Ion Channel Modulators Acting on the GABAA Receptor

Joesch¹,

Guevarra²,

Parel³

et al. 2008

SLAS Discovery

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“…Using this as a template, computer-generated models of ligandbinding pockets of Cys loop receptors, combined with previous data from structure-activity studies, have identified important features of these pockets and on the orientation of agonists and antagonists when located in their binding sites (7)(8)(9)(10)(11)(12)(13). Generating an accurate representation of the orientation of GABA in the GABA C receptor-binding site could identify the processes involved in ligand recognition at this receptor and would also assist in drug design; current data indicate that drugs acting on GABA C receptors could possibly be used to treat visual, sleep, and cognitive disorders (4,14).It has recently been shown that Tyr-198 forms a cationinteraction with the positive amine of GABA (15), and thus we can confidently locate this part of the GABA molecule close to this residue. The aim of this study was to locate the other end of GABA, the carboxylate group, in the binding site.…”

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confidence: 99%

Locating the Carboxylate Group of GABA in the Homomeric rho GABAA Receptor Ligand-binding Pocket

Harrison¹,

Lummis

2006

Journal of Biological Chemistry

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GABA3 is the major inhibitory neurotransmitter in the mammalian central nervous system (1). It mediates its effects via both ionotropic (GABA A ) and metabotropic (GABA B ) receptors. GABA C receptors are a subfamily of GABA A receptors and are sometimes referred to as GABA receptors, because the first subunit identified from this class of receptor was called 1 (2). These receptors have been separated from "classic" GABA A receptors because of their distinct pharmacological properties;GABA C receptor-mediated responses are not inhibited by bicuculline (the classic competitive GABA A receptor antagonist) nor induced by baclofen (the classic GABA B receptor agonist). In addition, 3-aminopropylphosphinic acid, a potent competitive GABA C receptor antagonist, acts as an agonist at the GABA B receptor and is inactive at the GABA A receptor, and GABA and trans-4-aminocrotonic acid are more potent agonists at GABA C receptors than GABA A or GABA B receptors (3). Thus there is clearly some variation in the structures of the different GABA-binding sites contained in these receptors, although the sequence homology between GABA A and GABA C receptor subunit sequences (Ͼ25%) indicates that their basic structures will be similar (structural homology is estimated at close to 80%) and will be similar to other members of the Cys loop family (4, 5).The lack of detailed structural information available for Cys loop receptors means that homology modeling is currently one of the best approaches to investigate possible molecular interactions between binding site residues and ligands. This approach has been made possible by the availability of the high resolution structure of the acetylcholine binding protein (AChBP), which is homologous to the extracellular domain of the nicotinic ACh receptor (6). Using this as a template, computer-generated models of ligandbinding pockets of Cys loop receptors, combined with previous data from structure-activity studies, have identified important features of these pockets and on the orientation of agonists and antagonists when located in their binding sites (7)(8)(9)(10)(11)(12)(13). Generating an accurate representation of the orientation of GABA in the GABA C receptor-binding site could identify the processes involved in ligand recognition at this receptor and would also assist in drug design; current data indicate that drugs acting on GABA C receptors could possibly be used to treat visual, sleep, and cognitive disorders (4,14).It has recently been shown that Tyr-198 forms a cationinteraction with the positive amine of GABA (15), and thus we can confidently locate this part of the GABA molecule close to this residue. The aim of this study was to locate the other end of GABA, the carboxylate group, in the binding site. This negatively charged end of GABA has been shown to interact with one or more positively charged residues in the GABA A receptor-binding pocket (16), and here we examine the role of positively charged and polar residues that are in or close to GABA in the GABA C receptor-binding...

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“…They are homomeric rather than heteromeric and therefore much simpler receptors. These properties make them important drug targets [42].…”

Section: Tpmpa and Related Compounds Competitive Antagonists Of Gabamentioning

confidence: 99%

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

Hinton¹,

Johnston²

2018

GABA and Glutamate - New Developments in Neurotransmission Research

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Agents that antagonize the action of GABA on ionotropic receptors are widely used to probe the function of this neurotransmiter. Three such agents are in common use: bicuculline, gabazine, and picrotoxinin. These three agents produce convulsions on systemic administration but act in signiicantly diferent ways. Bicuculline is a competitive antagonist of GABA A receptors. Gabazine is also a competitive antagonist of GABA A receptors, interacting with diferent residues on the receptors. Picrotoxinin is a noncompetitive antagonist acting on the chloride channel of GABA A and several other ionotropic CYSloop receptors including glycine, GABA C , and 5-HT 3 receptors. Many other structurally diverse agents are now known to act as GABA receptor antagonists, providing opportunities for the discovery of agents with selectivity for the myriad of ionotropic GABA receptors. TPMPA is a selective antagonist for GABA C receptors, which are insensitive to bicuculline. Like TPMPA, many antagonists of ionotropic GABA receptors are not convulsants, indicating that there is still much to be learnt about GABA function in the brain from the study of such agents and their possible therapeutic uses. The most recently discovered GABA A receptor nonconvulsive antagonist is S44819, which is subtype selective for α5-containing receptors, and is arousing much interest in relation to cognition.

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GABAC Receptors as Drug Targets

Cited by 80 publications

References 84 publications

Use of FLIPR Membrane Potential Dyes for Validation of High-Throughput Screening with the FLIPR and μARCS Technologies: Identification of Ion Channel Modulators Acting on the GABAA Receptor

Use of FLIPR Membrane Potential Dyes for Validation of High-Throughput Screening with the FLIPR and μARCS Technologies: Identification of Ion Channel Modulators Acting on the GABAA Receptor

Locating the Carboxylate Group of GABA in the Homomeric rho GABAA Receptor Ligand-binding Pocket

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

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