Subtype selectivity of α+β− site ligands of GABAA receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors. (25th April 2013)

• Record Type: Journal Article
• Authors: Varagic, Zdravko; Ramerstorfer, Joachim; Huang, Shengming; Rallapalli, Sundari; Sarto‐Jackson, Isabella; Cook, James; Sieghart, Werner; Ernst, Margot
• Is Part Of: British journal of pharmacology. Volume 169:Number 2(2013:May)
• Page Start: 384
• Page End: 399
• Publication Date: 2013-04-25
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12153
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12153-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>GABA<sub>A</sub> receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2‐(4‐methoxyphenyl)‐2<italic>H</italic>‐pyrazolo[4, 3‐<italic>c</italic>]quinolin‐3(5<italic>H</italic>)‐one) elicits a strong and subtype‐dependent enhancement of GABA‐induced currents via a novel drug‐binding site at extracellular αx+βy− (x = 1–6, y = 1–3) interfaces. Here, we investigated 16 structural analogues of CGS 9895 for their ability to modulate GABA‐induced currents of various GABA<sub>A</sub> receptor subtypes.</p> </sec> <sec id="bph12153-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Recombinant GABA<sub>A</sub> receptor subtypes were expressed in <italic>Xenopus laevis</italic> oocytes and investigated by the two‐electrode voltage clamp method.</p> </sec> <sec id="bph12153-sec-0003" sec-type="section"> <title>Key Results</title> <p>Most of the compounds investigated were able to modulate GABA‐induced currents of αβ and αβγ receptors to a comparable extent, suggesting that the effect of these drugs is not dependent on the benzodiazepine site of GABA<sub>A</sub> receptors. Steric hindrance experiments demonstrated that these compounds exert their action predominantly via the αx+βy− (x = 1–6, y = 1–3) interfaces. Whereas some compounds are unselectively modulating a broad range of receptor subtypes, other compounds feature remarkable functional selectivity for the α6β3γ2 receptor, or behave as null modulators at some receptor subtypes investigated.</p> </sec> <sec id="bph12153-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>Pyrazoloquinolinones and pyrazolopyridinones represent the first prototypes of drugs exerting benzodiazepine‐like modulatory effects via the α+β− interface of GABA<sub>A</sub> receptors. The discovery of modulators with functional subtype selectivity at this class of binding sites provides a highly useful tool for the investigation of α6β2/3γ2 receptor function, and may lead to novel therapeutic principles.</p> </sec> <sec id="bph12151-sec-1001" sec-type="relatedArticles"> <title>Linked Article</title> <p>This article is accompanied by Varagic <italic>et al</italic>., pp. 371–383 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12151</p> </sec> </abstract>