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Identification of novel positive allosteric modulators and null modulators at the GABA A receptor α+β− interface
Author(s) -
Varagic Zdravko,
Wimmer Laurin,
Schnürch Michael,
Mihovilovic Marko D,
Huang Shengming,
Rallapalli Sundari,
Cook James M,
Mirheydari Pantea,
Ecker Gerhard F,
Sieghart Werner,
Ernst Margot
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12151
Subject(s) - gabaa receptor , allosteric regulation , gabaa rho receptor , receptor , allosteric modulator , pharmacology , binding site , xenopus , biophysics , chemistry , ligand gated ion channel , biology , neuroscience , ion channel , biochemistry , gene
GABAA 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)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) acts as a null modulator (antagonist) at the high affinity benzodiazepine binding site, but in addition elicits a strong enhancement of GABA-induced currents via a novel drug binding site at the extracellular α+β- interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the α1+β3- interface of GABAA receptors.