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The central nervous system effects of the partial GABA ‐ A α 2,3 ‐selective receptor modulator AZD7325 in comparison with lorazepam in healthy males
Author(s) -
Chen Xia,
Jacobs Gabriël,
Kam Marieke,
Jaeger Judith,
Lappalainen Jaakko,
Maruff Paul,
Smith Mark A.,
Cross Alan J.,
Cohen Adam,
Gerven Joop
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12413
Subject(s) - lorazepam , gabaa receptor , pharmacodynamics , crossover study , pharmacology , placebo , benzodiazepine , visual analogue scale , anesthesia , chemistry , medicine , receptor , pharmacokinetics , alternative medicine , pathology
Aims AZD 7325 is a novel α 2,3 ‐subtype‐selective partial GABA ‐ A ‐receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD 7325 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 AZD 7325 was compared with lorazepam by plotting saccadic peak velocity change from baseline ( ΔSPV ) against body sway (Δ S way) and visual analogue scale for alertness(Δ VAS 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 < 0.05 vs. placebo), neither dose of AZD 7325 induced statistically significant effects on any pharmacodynamic measurements. Lorazepam‐induced SPV‐reduction was linearly related to changes in other neurophysiologic biomarkers. In contrast, the slopes of the regression lines were flatter for AZD 7325, particularly for the Δlog( S way) − Δ SPV relation (estimate slope, AZD7 325 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 Δ VAS alertness − Δ SPV relationship (0.01855 vs. 0.08216, −0.06360 [−0.1046, −0.02257], P = 0.0024). AZD 7325 10 mg and lorazepam induced different response patterns on VAS ‘feeling high’ and electro‐encephalography. Conclusion The characteristic Δ SPV ‐relative effect profiles of AZD 7325 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.