Abstract

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 GABA_A receptors containing α₁(K_i = 6.8 nM) and α₂(K_i = 12.3 nM) subunits, and weaker affinity for α₅-containing GABA_A receptors (K_i = 117 nM). Studies on recombinant rat GABA_A receptors confirm these data (K_i, α₁β₂γ₂ = 17, α₂β₂γ₂ = 73, α₅β₃γ₂ = 215 nM) and indicate intermediate affinity for the α₃β₂γ₂ subtype (K_i = 80 nM). SL651498 behaves as a full agonist at recombinant rat GABA_A receptors containing α₂ and α₃ subunits and as a partial agonist at recombinant GABA_A 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 GABA_A α₂ subtype in regulating anxiety and suggests that selectively targeting GABA_A receptor subtypes can lead to drugs with increased clinical specificity.