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Vol. 298, Issue 2, 753-768, August 2001

SL651498: An Anxioselective Compound with Functional Selectivity for alpha 2- and alpha 3-Containing gamma -Aminobutyric AcidA (GABAA) Receptors

Guy Griebel, Ghislaine Perrault, Jacques Simiand, Caroline Cohen, Patrick Granger, Michel Decobert, Dominique Françon, Patrick Avenet, Henri Depoortere, Suon Tan, André Oblin, Hans Schoemaker, Yannick Evanno, Mireille Sevrin, Pascal George and Bernard Scatton

CNS Research Department, Discovery Research, Sanofi~Synthelabo, Bagneux, France

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 alpha 1 (Ki = 6.8 nM) and alpha 2 (Ki = 12.3 nM) subunits, and weaker affinity for alpha 5-containing GABAA receptors (Ki = 117 nM). Studies on recombinant rat GABAA receptors confirm these data (Ki, alpha 1beta 2gamma 2 = 17, alpha 2beta 2gamma 2 = 73, alpha 5beta 3gamma 2 = 215 nM) and indicate intermediate affinity for the alpha 3beta 2gamma 2 subtype (Ki = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABAA receptors containing alpha 2 and alpha 3 subunits and as a partial agonist at recombinant GABAA receptors expressing alpha 1 and alpha 5 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 alpha 2 subtype in regulating anxiety and suggests that selectively targeting GABAA receptor subtypes can lead to drugs with increased clinical specificity.

0022-3565/01/2982-0753$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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