The central nervous system effects of the partial GABA-Aalpha2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males.

Article Details

Citation

Chen X, Jacobs G, de Kam M, Jaeger J, Lappalainen J, Maruff P, Smith MA, Cross AJ, Cohen A, van Gerven J

The central nervous system effects of the partial GABA-Aalpha2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males.

Br J Clin Pharmacol. 2014 Dec;78(6):1298-314. doi: 10.1111/bcp.12413.

PubMed ID
24802722 [ View in PubMed
]
Abstract

AIMS: AZD7325 is a novel alpha2,3 -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 (DeltaSPV) against body sway (DeltaSway) and visual analogue scale for alertness(DeltaVASalertness ). This analysis has previously been used to identify alpha2,3 -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 Deltalog(Sway) -DeltaSPV 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 DeltaVASalertness -DeltaSPV 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 DeltaSPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to alpha2,3 -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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
AZD-7325Gamma-aminobutyric acid receptor subunit alpha-2ProteinHumans
Yes
Positive allosteric modulator
Details
AZD-7325Gamma-aminobutyric acid receptor subunit alpha-3ProteinHumans
Yes
Positive allosteric modulator
Details