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

Article date: 2000/10/13

PubMed ID: 2445971

Journal name: British journal of pharmacology (ISSN: 0007-1188)


(+)-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 alpha1beta2gamma2 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 microM of the benzodiazepine antagonist Ro 15-1788, and (+)-ROD188 also stimulated currents mediated by alpha1beta2, indicating a major mechanism of action different from that of benzodiazepines. Allosteric stimulation by (+)-ROD188 was similar in alpha1beta2N265S as in unmutated alpha1beta2, while that by loreclezole was strongly reduced. (+)-ROD188 also strongly stimulated currents elicited by either pentobarbital or 5alpha-pregnan-3alpha-ol-20-one (3alpha-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 alpha6beta2gamma2 (alpha6beta2gamma2>alpha1beta2gamma2=alpha5beta2gamma2++ +>alpha2beta2ga mma2= alpha3beta2gamma2), 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 microM (+)-ROD188, indicating an enhanced synaptic inhibitory transmission.

Author List: Thomet U, Baur R, Razet R, Dodd R H, Furtmüller R, Sieghart W, Sigel E

Publication Types: Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: 1-(2,3,4,5-tetrahydro-5-oxo-2-furyl)-2-N-(p-toluenesulfonyl)-1,2,3,4-tetrahydroisoquinoline; Furans; GABA Modulators; Isoquinolines; Receptors, GABA-A; Tetrahydroisoquinolines; Triazoles; Benzodiazepines; loreclezole;

Mesh terms: Action Potentials/drug effects; Allosteric Regulation; Animals; Benzodiazepines/pharmacology; Cells, Cultured; Female; Furans/pharmacology; GABA Modulators/pharmacology; Hippocampus/drug effects; Humans; Isoquinolines/pharmacology; Rats; Rats, Sprague-Dawley; Receptors, GABA-A/drug effects; Tetrahydroisoquinolines; Triazoles/pharmacology; Xenopus laevis;

Citations: - Stimulation of receptors of gamma-aminobutyric acid modulates the release of cholecystokinin-like immunoreactivity from slices of rat neostriatum.

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