The central nervous system effects of the partial GABA‐Aα2,3‐selective receptor modulator AZD7325 in comparison with lorazepam in healthy males

摘要

Aims AZD7325 is a novel α_2,3-subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD7325 2?mg and 10?mg on the central nervous system (CNS) compared with placebo and lorazepam 2?mg. Methods This double-blind, randomized, four way crossover study enrolled 16 healthy males and administered two validated CNS test batteries to measure drug effects on cognitive, neurophysiologic and psychomotor function and subjective feelings. The pharmacological selectivity of AZD7325 was compared with lorazepam by plotting saccadic peak velocity change from baseline (ΔSPV) against body sway (ΔSway) and visual analogue scale for alertness(ΔVAS_alertness). This analysis has previously been used to identify α_2,3-subtype-selectivity. Results In contrast with the robust impairment caused by lorazepam (all P ?ΔSPV relation (estimate slope, AZD7325 10?mg vs . lorazepam, difference [95% confidence interval], P value ?0.00036 vs. ?0.00206, 0.001704 [0.000639, 0.002768], P = 0.0018) and the ΔVAS_alertness?ΔSPV relationship (0.01855 vs. 0.08216, ?0.06360 [?0.1046, ?0.02257], P = 0.0024). AZD7325 10?mg and lorazepam induced different response patterns on VAS ‘feeling high’ and electro-encephalography. Conclusion The characteristic ΔSPV-relative effect profiles of AZD7325 vs . lorazepam suggest anxio-selectivity related to α_2,3-selective GABA_A agonism. However, exploration of higher doses may be warranted. The paucity of effects on most CNS?PD parameters also indicates a mitigated side effect pattern, with potentially lower cognitive and neurophysiological side effect burden than non-selective benzodiazepines.