Various a2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are\r\nexpected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines.\r\nSeveral a2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery\r\naddressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2mg was\r\nthe comparator in three studies. Three a2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one a1-selective\r\nGABAA agonists (zolpidem), and another full agonist (alprazolam) were examined. Pharmacological selectivity was assessed by\r\ndetermination of regression lines for the change from baseline of saccadic-peak-velocity- (?SPV-) relative effect, relative to changes\r\nin different pharmacodynamic endpoints (?PD). SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes\r\nof the ?SPV-?PD relations were consistently lower with the a2,3 selective GABA-A agonists than with lorazepam, indicating that\r\ntheir PD effects are less than their SPV-effects. The ?SPV-?PD relations of lorazepam were comparable to alprazolam. Zolpidem\r\nshowed relatively higher impairments in ?PD relative to ?SPV, but did not significantly differ from lorazepam. These PD results\r\nsupport the pharmacological selectivity of the a2,3-selective GABA-A agonists, implying an improved therapeutic window.
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