title: A novel positive allosteric modulator of the GABA(A) receptor: the action of (+)-ROD188.
abstract: (+)-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.
authors.affiliation: Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Thomet
authors.forename: R
authors.initials: R
authors.lastname: Baur
authors.forename: R
authors.initials: R
authors.lastname: Razet
authors.forename: R H
authors.initials: RH
authors.lastname: Dodd
authors.forename: R
authors.initials: R
authors.lastname: Furtmüller
authors.forename: W
authors.initials: W
authors.lastname: Sieghart
authors.forename: E
authors.initials: E
authors.lastname: Sigel
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000494:Allosteric Regulation; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005663:Furans / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D044005:Tetrahydroisoquinolines; D014230:Triazoles / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C416384:1-(2,3,4,5-tetrahydro-5-oxo-2-furyl)-2-N-(p-toluenesulfonyl)-1,2,3,4-tetrahydroisoquinoline; D005663:Furans; D018757:GABA Modulators; D007546:Isoquinolines; D011963:Receptors, GABA-A; D044005:Tetrahydroisoquinolines; D014230:Triazoles; D001569:Benzodiazepines; C066440:loreclezole