Various subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2？mg was the comparator in three studies. Three -selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one -selective GABAA agonists (zolpidem), and another full agonist (alprazolam) were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV-) relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD). SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the -selective GABA-A agonists, implying an improved therapeutic window. 1. Introduction Anxiety is a psychological and physiological state with somatic, emotional, cognitive, and behavioral components [1], which dominates thinking and leads to disturbance of daily functioning. Serotonergic antidepressants, either selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), are currently prescribed as the 1st-line treatment for several anxiety disorders. However, the slow onset of therapeutic effect and the presence of sexual side effects prevent these drugs from more extensive use and lead to lack of treatment compliance [2]. Moreover, SSRIs/SNRIs cause transient increase of anxiety during the first few weeks of administration. All these clinical experiences provide space for the use of benzodiazepines (BZDs) in acute anxiety episodes. Benzodiazepines are the most commonly prescribed anxiolytic drugs, although treatment guidelines generally limit their use to several weeks to prevent the occurrence of tolerance and dependence. Benzodiazepines are allosteric modulators of the GABAA receptors that affect the central nervous system
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