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 alpha(1) (K(i) = 6.8 nM) and alpha2 (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing
GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat
GABA(A) receptors confirm these data (K(i), alpha1beta2gamma2 = 17, alpha2beta2gamma2 = 73, alpha5beta3gamma2 = 215 nM) and indicate intermediate affinity for the alpha3beta2gamma2 subtype (K(i) = 80 nM).
SL651498 behaves as a full agonist at recombinant rat
GABA(A) receptors containing alpha2 and alpha3 subunits and as a partial agonist at recombinant
GABA(A) receptors expressing alpha1 and alpha5 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 > or = 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) alpha2 subtype in regulating anxiety and suggests that selectively targeting
GABA(A) receptor subtypes can lead to drugs with increased clinical specificity.