title: Partial GABA agonist activity of SR 95531 on the binding of [35S]TBPS, [3H]DMCM and [3H]lormetazepam to rat brain membranes.
abstract: A recently developed series of pyridazinyl-GABA derivatives has been classified as GABA antagonists in electrophysiological, behavioral and biochemical experiments. These substances seemed superior to the classical GABA antagonist bicuculline because of their water-solubility, high potency and apparent selectivity for GABAA receptors. In the present study the most potent representative of this class, SR 95531 almost completely reversed the stimulatory or inhibitory effect of GABA on [3H]lormetazepam and [35S]TBPS binding, respectively. To a lesser extent, it antagonized the inhibition of [3H]DMCM binding by GABA. However, the interaction of SR 95531 with the GABA receptor seems to be of a complex nature since the compound enhanced the binding of [3H]lormetazepam by 28% at 37 degrees in the presence of 200 mM Cl-. Bicuculline inhibited [3H]lormetazepam binding under these conditions, presumably by antagonizing the effect of residual endogenous GABA. Similar to GABA and THIP, SR 95531 potently inhibited the binding of [3H]DMCM and [35S]TBPS, suggesting SR 95531 to be a partial agonist at the GABAA receptor.
authors.affiliation: Research Laboratories of Schering AG, West Berlin, Federal Republic of Germany.
authors.forename: L N
authors.initials: LN
authors.lastname: Zimmermann
authors.forename: H H
authors.initials: HH
authors.lastname: Schneider
authors.forename: D N
authors.initials: DN
authors.lastname: Stephens
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D001921:Brain / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002243:Carbolines / Q000378:metabolism*; D018756:GABA Antagonists; D066298:In Vitro Techniques; D008140:Lorazepam / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D002243:Carbolines; D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; C049853:gabazine; C023842:lormetazepam; D008140:Lorazepam