SL651498, a GABA_A Receptor Agonist with Subtype‐Selective Efficacy, as a Potential Treatment for Generalized Anxiety Disorder and Muscle Spasms

Abstract

SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2, 9-dihydro-1H-pyrido [3,4-b]indol-1-one) was identified as a drug development candidate from a research program designed to discover subtype-selective GABA A receptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABA A receptors containing á 1 (K i = 6.8 nM) and á 2 (K i = 12.3 nM) subunits, and weaker affinity for á 5 -containing GABA A receptors (K i = 117 nM). Studies on recombinant rat GABA A receptors confirm these findings and indicate intermediate affinity for the á 3 â 2 ã 2 subtype. SL651498 behaves as a full agonist at recombinant rat GABA A receptors containing á 2 and á 3 subunits, and as a partial agonist at recombinant GABA A receptors expressing á 1 and á 5 subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic-like activity (MED: 30 to 100 mg /kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential 3

Selective anxiolysis produced by ocinaplon, a GABA A receptor modulator

“…First, it is possible that ocinaplon and benzodiazepines act on different GABA A receptor subtypes such that ocinaplon produces its anxiolytic effects through actions on ␣1-containing complexes, whereas benzodiazepines and perhaps other structural classes of compounds (11,12) produce anxiolytic effects through actions on ␣2-containing (GABA A2 ) receptors. This hypothesis is presently 5.…”

“…Rather, a combination of high relative potency and high relative efficacy at certain receptor subtypes would seem to more parsimoniously explain its anxioselective properties. Finally, although studies using knock-in mice indicate that GABA A1 receptors contribute to the sedative and anticonvulsant properties of benzodiazepines (36,37), pharmacological studies using a selective GABA A1 antagonist (38,39) indicate that the anticonflict (but not the motor impairing) actions of diazepam (11,40) are mediated via GABA A1 receptors. There are other significant inconsistencies between data obtained in knock-in mice and pharmacological studies using subtype selective pharmacological agents in wild type animals (41).…”

“…The identification of novel molecules acting at the benzodiazepine recognition site of the GABA A receptor began Ͼ25 years ago (9,10), and remains an area of intense interest (2,5,11,12). The impetus for identifying such molecules was the discovery that the triazolopyridazine, CL 218,872 (9,10), exhibited selectivity for ''Type I'' benzodiazepine receptors (subsequently identified as GABA A receptors containing an ␣1-subunit; refs.…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…Additionally, the study indicated that SL651498 produced ataxia, muscle weakness or sedation at doses much higher than those producing anxiolytic-like activity. No appearance of tolerance to its anticonvulsant effects or physical dependence was observed in mice [357]. SL651498 elicits anxiolytic-like effects similar to conventional BZs.…”

Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

“…Unlike full agonists, partial agonists of the GABA A receptor, particularly those that are subtype-selective (Low et al, 2000;Mohler et al, 2002;Griebel et al, 2003), may afford concurrently the desired anxiolytic effects of a benzodiazepine while minimizing or eliminating its unwanted side effects, resulting in a superior safety profile for the general and chronic treatment of GAD (Lader, 1994).…”