An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

摘要: Various 𝛼2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds expected be anxiolytic with fewer undesirable side effects, compared nonselective like benzodiazepines. Several and have been examined 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 three studies. Three 𝛼2,3-selective GABAA (i.e., TPA023, TPACMP2, SL65.1498), one 𝛼1-selective (zolpidem), another full agonist (alprazolam) examined. Pharmacological selectivity assessed by determination of regression lines for change baseline saccadic-peak-velocity- (ΔSPV-) relative effect, changes pharmacodynamic endpoints (ΔPD). SPV chosen its sensitivity anxiolysis Slopes ΔSPV-ΔPD relations consistently lower than lorazepam, indicating that their PD effects less SPV-effects. The lorazepam comparable alprazolam. Zolpidem showed relatively higher impairments ΔPD ΔSPV, but did not significantly differ lorazepam. results support pharmacological agonists, implying an improved therapeutic window.