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

Advances in Pharmacological Sciences
Xia ChenJ M A van Gerven

Abstract

Various α(2,3) 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 α(2,3) 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 α(2,3)-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one α(1)-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 α(2,3) 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 alpra...Continue Reading

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Citations

Nov 21, 2018·Psychophysiology·Stefan DuschekUlrich Ettinger
Dec 7, 2016·British Journal of Clinical Pharmacology·Xia ChenJoop van Gerven
Feb 13, 2021·British Journal of Clinical Pharmacology·Jonas M den HeijerGeert Jan Groeneveld

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