1. Centre for Human Drug Research | Zernikedreef 8 | 2333 CL Leiden | The Netherlands | Tel +31 71 52 46 400 | info@chdr.nl | www.chdr.nl Chen, X 1,2, Jaeger, J 3 *, Lappalainen, J 4, Maruff, P 3, Smith, MA 5 *, Cross, AJ 4, van Gerven, JMA 2 1 Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China; 2 Centre for Human Drug Research,Leiden, The Netherlands; 3 Cogstate, Melbourne Australia and New Haven CT, USA; 4 AstraZeneca, R&D, Wilmington Delaware and Cambridge MA; 5 Shire Pharmaceuticals, PA, USA ■ CONCLUSIONS ■ The characteristic ΔSPV-relative effect profiles of AZD7325 vs. lorazepam suggests anxio-selectivity related to α 2,3 -selective GABA A agonism. However, exploration of higher doses may be warranted. ■ The lack of effects on most CNS-PD parameters suggests lower cognitive and neurophysiological side-effect burden than non-selective benzodiazepines. A study with a partial subtype selective GABA A α 2,3 agonist, using quantitative pharmacodynamic measurements in healthy subjects ■ INTRODUCTION Does AZD7325, a novel α 2,3 -subtype selective GABA A modulator produce a benzodiazepine-like profile on cognition and neurophysiologic biomarkers at doses that result in high GABA A receptor occupancy? ■ AIM To investigate the effects of AZD7325 on cognitive, visuo- motor, neurophysiological and postural stability measures relative to lorazepam at doses that result in comparable or higher occupancy. ■ METHODS ■ Design: single-dose, randomized, double-blind, 4-way crossover study in 16 healthy men ■ Treatments: AZD7325 10mg, AZD7325 2 mg, Lorazepam 2 mg, Placebo ■ CogState battery: ■ RESULTS ■ Neither dose of AZD7325 affected VAS alertness, SPV, sway, smooth pursuit, tracking, or any cognitive measures (Figure 1), which were all robustly impaired by lorazepam 2mg (all p<0.05). ■ The slopes of the regression lines were flatter for AZD7325, particularly for the ΔLog(Sway)-ΔSPV relation and the ΔVAS alertness -ΔSPV relation, compared to lorazepam (Figure 2). ■ CNS-PD test battery: ■ Neurophysiological function: saccadic peak velocity (SPV), smooth pursuit ■ Postural balance: Body sway ■ Eye-hand coordination: Adaptive tracking ■ Subjective effect: Visual analogue scales, VAS alertness AZD7325 2 mg AZD7325 10 mg Δ VAS alertness Δ log(Sway) Figure 2.:ΔSPV-ΔVAS alertness and ΔSPV-Δlog(Sway) relation Δ SPV Figure 1:Group mean (+SE) performance on CogState measures at each of the time points. Note: Detection and Chase test profiles were very similar to that observed on Identification task, shown above. Poster copy The authors report no conflicts of interest for this work 2.64 2.66 2.68 2.70 2.72 2.74 2.76 2.78 2.80 2.82 2.84 2.86 -3-20123456789 hours group mean (SE) speed (log10RT) low high loraz placebo 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 -3-20123456789 hours group mean (SE) prop correct (arcsine) low high loraz placebo Visual Learning Identification 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 -3-20123456789 hours group mean (SE) Errors) low high loraz placebo Executive Functioning