Central action of ipsapirone, a new anxiolytic drug, on serotoninergic, noradrenergic and dopaminergic functions

Abstract

Ipsapirone (TVX Q 7821, 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride), a new anxiolytic drug in respect of the evaluation of its effect on central 5-hydroxy-tryptamine (5-HT), noradrenaline and dopamine functions was studied. It was found that ipsapirone inhibits induced by 8-OH-DPAT and 5-methoxy-dimethyltryptamine (agonists of 5-HT_1A receptors) behavioural effects (flat body posture and forepaw treading) in normal and reserpinized rats. Ipsapirone partly inhibited in rats but not in mice the 8-OH-DPAT-induced hypothermia. Ipsapirone, administered at high doses, decreased the body temperature in rats and mice, inhibited the 5-hydroxytryptophan-induced head twitches in mice and the tryptamine-induced convulsions and tremor in rats. In the hind limb flexor reflex preparation of the spinal rat only high doses of the drug inhibited stimulation induced by quipazine, m-chlorphenylpiperazine, 8-OH-DPAT and St 587 (an agonist ofα ₁-adrenoceptors). Ipsapirone did not block the fenfluramine- and m-chlorphenylpiperazine-induced hyperthermia in rats at an ambient temperature of 28‡C. The drug did not affect clonidine-induced sedation and inconsiderably attenuated clonidine-induced hypothermia in mice. It attenuated the d-amphetamine-induced locomotor hyperactivity in mice and rats but, given alone, decreased the locomotor activity. The obtained results indicate that ipsapirone exhibits 5-HT_1A antagonistic effect, and only at high doses it can also produce an inhibitory effect on 5-HT₂ and theα ₁adrenergic function.