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

¹ Centre for Human Drug Research, Leiden, The Netherlands.
² MSD (Europe) Inc., Brussels, Belgium.
³ MRL, West Point, PA, USA.

^* To whom correspondence should be addressed.

	Abstract

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

First published on November 8, 2006, doi:10.1177/0269881106072343

Journal of Psychopharmacology 2007;21:374.

A more recent version of this article appeared on June 1, 2007


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. de Haas, K. Franson, J. Schmitt, A. Cohen, J. Fau, C Dubruc, and J. van Gerven The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A 2,3 selective agonist, in comparison with lorazepam in healthy volunteers J Psychopharmacol, August 1, 2009; 23(6): 625 - 632. [Abstract] [PDF]

				J. Bailey, A Papadopoulos, K Seddon, and D. Nutt A comparison of the effects of a subtype selective and non-selective benzodiazepine receptor agonist in two CO2 models of experimental human anxiety J Psychopharmacol, March 1, 2009; 23(2): 117 - 122. [Abstract] [PDF]

				N. R. Mirza, J. S. Larsen, C. Mathiasen, T. A. Jacobsen, G. Munro, H. K. Erichsen, A. N. Nielsen, K. B. Troelsen, E. O. Nielsen, and P. K. Ahring NS11394 [3'-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABAA Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 954 - 968. [Abstract] [Full Text] [PDF]

				D. A. Lewis, R. Y. Cho, C. S. Carter, K. Eklund, S. Forster, M. A. Kelly, and D. Montrose Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia Am J Psychiatry, December 1, 2008; 165(12): 1585 - 1593. [Abstract] [Full Text] [PDF]