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The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety

1993; Elsevier BV; Volume: 234; Issue: 1 Linguagem: Inglês

10.1016/0014-2999(93)90710-y

1879-0712

B. Costall, A.M. Domeney, M.E. Kelly, D.M. Tomkins, Robert J. Naylor, Erik H.F. Wong, William L. Smith, R.L. Whiting, Richard M. Eglen,

Nicotinic Acetylcholine Receptors Study

The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H-benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.