Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAAα2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers

TPA023, a GABA(A) alpha 2,3 alpha subtype-selective partial agonist, is expected to have comparable anxiotytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the al subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazeparn 2 mg (therapeutic anxioLytic dose). Twelve healthy male volunteers participated in this p[acebo-controlled, double-blind, doubledummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on postural stability and cognition were assessed using body sway and a standardized battery of neurophysiotogicat memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of torazepam. In contrast to lorazepam, TPA023 had no detectable effects on saccadic latency or inaccuracy. Also unlike torazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazeparn, at doses that were equipotent with regard to effects on saccadic peak velocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABA(A) receptor subtypes.