PT - JOURNAL ARTICLE AU - Griebel, Guy AU - Perrault, Ghislaine AU - Simiand, Jacques AU - Cohen, Caroline AU - Granger, Patrick AU - Decobert, Michel AU - Françon, Dominique AU - Avenet, Patrick AU - Depoortere, Henri AU - Tan, Suon AU - Oblin, André AU - Schoemaker, Hans AU - Evanno, Yannick AU - Sevrin, Mireille AU - George, Pascal AU - Scatton, Bernard TI - SL651498: An Anxioselective Compound with Functional Selectivity for α<sub>2</sub>- and α<sub>3</sub>-Containing γ-Aminobutyric Acid<sub>A</sub> (GABA<sub>A</sub>) Receptors DP - 2001 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 753--768 VI - 298 IP - 2 4099 - http://jpet.aspetjournals.org/content/298/2/753.short 4100 - http://jpet.aspetjournals.org/content/298/2/753.full SO - J Pharmacol Exp Ther2001 Aug 01; 298 AB - SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one] is a novel pyridoindole derivative that displays high affinity for rat native GABAA receptors containing α1(Ki = 6.8 nM) and α2(Ki = 12.3 nM) subunits, and weaker affinity for α5-containing GABAA receptors (Ki = 117 nM). Studies on recombinant rat GABAA receptors confirm these data (Ki, α1β2γ2 = 17, α2β2γ2 = 73, α5β3γ2 = 215 nM) and indicate intermediate affinity for the α3β2γ2 subtype (Ki = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABAA receptors containing α2 and α3 subunits and as a partial agonist at recombinant GABAA receptors expressing α1and α5 subunits. SL651498 elicited anxiolytic-like activity similar to that of diazepam [minimal effective dose (MED): 1–10 mg/kg, i.p.] in three conflict models, in the elevated plus-maze, the light/dark test, and the defense test battery in rats and mice. Results from activity tests and electroencephalogram analysis indicated that SL651498 induced muscle weakness, ataxia, or sedation at doses much higher than those producing anxiolytic-like activity (MED ≥ 30 mg/kg, i.p.). Repeated treatment for 10 days with SL651498 (30 mg/kg, i.p., b.i.d.) in mice was not associated with the development of tolerance to its anticonvulsant effects or physical dependence. Furthermore, SL651498 was much less active than diazepam in potentiating the depressant effects of ethanol in mice. The “anxioselective” profile of SL651498 points to a major role for GABAA α2 subtype in regulating anxiety and suggests that selectively targeting GABAA receptor subtypes can lead to drugs with increased clinical specificity. The American Society for Pharmacology and Experimental Therapeutics