Abstract
Benzodiazepines (BZs) are prescribed for a variety of disorders, including those involving anxiety and sleep, but have unwanted side effects that limit their use. Elucidating the GABAA receptor mechanisms underlying the behavioral effects of BZs will help develop new drugs having both maximum clinical benefit and minimum adverse side effects. A recently developed compound is SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one], which is a full agonist at GABAA receptors containing α2and α3 subunits and a partial agonist at GABAA receptors containing α1 and α5 subunits. We assessed the ability of SL651498 to engender anxiolytic-like, motor, and subjective effects characteristic of BZ-type drugs in nonhuman primates. Anxiolytic-like activity was assessed with a conflict procedure in rhesus monkeys. Motor effects were evaluated in squirrel monkeys using observational techniques, and the subjective effects of SL651498 were assessed in squirrel monkeys trained to discriminate the nonselective BZ triazolam from saline. SL651498 engendered anxiolytic-like effects similar to conventional BZs. In addition, SL651498 fully induced muscle relaxation, but unlike conventional BZs, engendered minimal ataxia. In drug discrimination studies, SL651498 partially substituted for triazolam. This effect was blocked with the α1 GABAA subtype-preferring antagonist β-CCT (β-carboline-3-carboxylate-t-butyl ester), implicating α1 GABAA effects receptors in the subjective of SL651498. Together, these studies suggest that compounds such as SL651498 that have high intrinsic efficacy at α2GABAA and/or α3GABAA receptors may have clinical potential as anxiolytics and muscle relaxants. Moreover, a compound with reduced efficacy at α1 GABAA and/or α5 GABAA receptors may lack some of the motor and subjective effects associated with conventional BZs.
Footnotes
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This work was supported by U.S. Public Health Services Grants DA11792, DA00499, and RR00168, as well as the National Institute of Mental Health Grant MH-46851. A preliminary report of these data was made at the 2004 Annual Meeting of the College on Problems of Drug Dependence.
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doi:10.1124/jpet.104.081612.
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ABBREVIATIONS: BZ, benzodiazepine; SL651498, 6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one; FR, fixed ratio; β-CCT, β-carboline-3-carboxylate-t-butyl ester; MS, maximum score; MD, minimally effective dose.
- Received December 3, 2004.
- Accepted January 31, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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