title: The central nervous system effects of the partial GABA-Aα2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males.
abstract: OBJECTIVE
  AZD7325 is a novel α2,3 -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(ΔVASalertness ). This analysis has previously been used to identify α2,3 -subtype-selectivity.
  
  
  RESULTS
  In contrast with the robust impairment caused by lorazepam (all P < 0.05 vs. placebo), neither dose of AZD7325 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 AZD7325, particularly for the Δlog(Sway) -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 ΔVASalertness -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.
  
  
  CONCLUSIONS
  The characteristic ΔSPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to α2,3 -selective GABAA 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.
authors.affiliation: Phase I Unit, Clinical Pharmacology Research Center (CPRC), Peking Union Medical College Hospital, Beijing, China; Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Gabriël
authors.initials: G
authors.lastname: Jacobs
authors.forename: Marieke
authors.initials: M
authors.lastname: de Kam
authors.forename: Judith
authors.initials: J
authors.lastname: Jaeger
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
authors.forename: Paul
authors.initials: P
authors.lastname: Maruff
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Cross
authors.forename: Adam
authors.initials: A
authors.lastname: Cohen
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D018757:GABA Modulators / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008140:Lorazepam / Q000494:pharmacology*; D008297:Male; D011963:Receptors, GABA-A / Q000187:drug effects
chemical_list: C576237:4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide; D018757:GABA Modulators; C484841:GABRA2 protein, human; D006574:Heterocyclic Compounds, 2-Ring; D011963:Receptors, GABA-A; D008140:Lorazepam
keywords: AZD7325; GABAergic; agonism; pharmacodynamic; selective