A novel positive allosteric modulator of the GABA A receptor: the action of (+)‐ROD188

(+)‐ROD188 was synthesized in the search for novel ligands of the GABA binding site. It shares some structural similarity with bicuculline. (+)‐ROD188 failed to displace [ 3 H]‐muscimol in binding studies and failed to induce channel opening in recombinant rat α1β2γ2 GABA A receptors functionally expressed in Xenopus oocytes. (+)‐ROD188 allosterically stimulated GABA induced currents. Displacement of [ 3 H]‐Ro15‐1788 indicated a low affinity action at the benzodiazepine binding site. In functional studies, stimulation by (+)‐ROD188 was little sensitive to the presence of 1 μ M of the benzodiazepine antagonist Ro 15‐1788, and (+)‐ROD188 also stimulated currents mediated by α1β2, indicating a major mechanism of action different from that of benzodiazepines. Allosteric stimulation by (+)‐ROD188 was similar in α1β2N265S as in unmutated α1β2, while that by loreclezole was strongly reduced. (+)‐ROD188 also strongly stimulated currents elicited by either pentobarbital or 5α‐pregnan‐3α‐ol‐20‐one (3α‐OH‐DHP), in line with a mode of action different from that of barbiturates or neurosteroids as channel agonists. Stimulation by (+)‐ROD188 was largest in α6β2γ2 (α6β2γ2>>α1β2γ2=α5β2γ2>α2β2γ2= α3β2γ2), indicating a unique subunit isoform specificity. Miniature inhibitory postsynaptic currents (mIPSC) in cultures of rat hippocampal neurons, caused by spontaneous release of GABA showed a prolonged decay time in the presence of 30 μ M (+)‐ROD188, indicating an enhanced synaptic inhibitory transmission.British Journal of Pharmacology (2000) 131 , 843–850; doi: 10.1038/sj.bjp.0703558