RT Journal Article SR Electronic T1 SL651498: An Anxioselective Compound with Functional Selectivity for α2- and α3-Containing γ-Aminobutyric AcidA (GABAA) Receptors JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 753 OP 768 VO 298 IS 2 A1 Griebel, Guy A1 Perrault, Ghislaine A1 Simiand, Jacques A1 Cohen, Caroline A1 Granger, Patrick A1 Decobert, Michel A1 Françon, Dominique A1 Avenet, Patrick A1 Depoortere, Henri A1 Tan, Suon A1 Oblin, André A1 Schoemaker, Hans A1 Evanno, Yannick A1 Sevrin, Mireille A1 George, Pascal A1 Scatton, Bernard YR 2001 UL http://jpet.aspetjournals.org/content/298/2/753.abstract 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