RT Journal Article
SR Electronic
T1 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
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