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Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA_{A 2,3} subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers

Centre for Human Drug Research, Leiden, The Netherlands,shaas{at}chdr.nl

S.J. de Visser

Centre for Human Drug Research, Leiden, The Netherlands

J.P. van der Post

Centre for Human Drug Research, Leiden, The Netherlands

M. de Smet

MSD (Europe) Inc., Brussels, Belgium

R.C. Schoemaker

Centre for Human Drug Research, Leiden, The Netherlands

B. Rijnbeek

Centre for Human Drug Research, Leiden, The Netherlands

A.F. Cohen

Centre for Human Drug Research, Leiden, The Netherlands

J.M. Vega

MRL, West Point, PA, USA

N.G.B. Agrawal

MRL, West Point, PA, USA

T.V. Goel

MRL, West Point, PA, USA

R.C. Simpson

MRL, West Point, PA, USA

L.K. Pearson

MRL, West Point, PA, USA

S. Li

MRL, West Point, PA, USA

M. Hesney

MRL, West Point, PA, USA

M.G. Murphy

MRL, West Point, PA, USA

J.M.A. van Gerven

Centre for Human Drug Research, Leiden, The Netherlands

TPA023, a GABA_A 2,3 subtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound Lacks efficacy at the 1 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 Lorazepam 2 mg (therapeutic anxioLytic dose). Twelve healthy maLe volunteers participated in this placebo-controlled, double-blind, double-dummy, 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 neurophysiological 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 Lorazepam. In contrast to Lorazepam, TPA023 had no detectabLe effects on saccadic Latency or inaccuracy. Also unlike Lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of Lorazepam, 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.

Key Words: TPA023 • selective partial GABA agonist • memory • body sway • saccadic eye movements • sedation • benzodiazepines

This version was published on June 1, 2007

Journal of Psychopharmacology, Vol. 21, No. 4, 374-383 (2007)
DOI: 10.1177/0269881106072343


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