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SR 140333 (1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl]-4-phenyl-1-azonia-bicyclo[2.2.2]octane , chloride), a potent non peptide ligand of the substance P (SP) NK1 receptor subtype with high affinity for NK1 receptors from both rat cortical membranes and human IM9 cells (Ki = 0.02 nM and 0.01 nM, respectively) was studied in vivo on various effects induced by NK1 agonists in rats and mice. SR 140333 given intraperitoneally (i.p.) in mice antagonized dose-dependently and in a stereoselective manner the scratching responses induced by intracerebroventricular SP and septide (ID50 = 0.73 and 0.08 mg/kg, respectively) and the turning behavior elicited by intrastriatal SP and septide (ID50 = 0.07 and 0.06 mg/kg, respectively). This compound had little effect on the scratching responses and the turning behavior elicited by [Sar9, Met(O2)11]-SP. When SR 140333 was coadministered with the peptide agonist, the compound reduced the scratching responses elicited by SP, [Sar9, Met(O2)11]-SP and septide injected intrathecally (i.t.) in mice (ID50 = 72.0, 64.3 and 52.5 ng i.t., respectively). SR 140333 antagonized the salivation induced by SP, [Sar9, Met(O2)11]-SP and septide in rats (ID50 = 0.13, 0.18 and 0.09 mg/kg i.p., respectively). SR 140333 abolished the facilitation of the tail-flick reflex induced by noxious heat in rats (total reversal at 0.06 mg/kg, i.p.). This compound was also found to inhibit the turning behavior induced by intrastriatal apomorphine in mice (ID50 = 0.1 mg/kg, i.p.). In conclusion, these results indicate that SR 140333 behaves as a potent, selective and centrally active NK1 receptor antagonist.

The biochemical, electrophysiological and behavioural effects of SR 31742A, a novel and selective ligand of sigma sites in brain, labelled with (+)-[3H]3PPP (Ki = 5.3 +/- 0.3 nM), were investigated in rodents and compared with those of DA antagonists having (haloperidol) or not (spiroperidol) a high affinity for sigma sites. Like haloperidol but unlike spiroperidol, SR 31742A, (ED50 = 0.065 mg/kg, i.p., and 0.21 mg/kg, p.o.) antagonized sigma-dependent turning behaviour in mice and inhibited (0.5 mg/kg, i.v.) the spontaneous firing of hippocampal (CA3) neurones in urethane-anaesthetized rats. In chloral hydrate-anaesthetized rats, like classical antipsychotic compounds, SR 31742A (0.625-5 mg/kg, i.p.) increased the number of spontaneously active A9 and A10 DA cells after single administration and produced an opposite effect after repeated injections. The drug SR 31742A reduced (2.5, 5, 10 mg/kg, i.p.) the hyperactivity elicited by various drugs including that produced by injection of (+)-amphetamine into the nucleus accumbens and impaired avoidance responses at doses (5, 10 mg/kg, i.p.), sparing escape behaviour. SR 31742A lacked affinity for DA receptors and neither did the compound induce catalepsy nor antagonize such effects elicited by apomorphine as climbing, hypothermia, stereotypy or the inhibition of firing of DA neurones. SR 31742A did not affect the basal metabolism of DA but at 10 mg/kg (i.p.) it significantly reduced the amphetamine-induced rise in levels of 3-MT in the striatum of mice. Together, these results indicate a modulatory role for sigma sites upon the activity of hippocampal and DA systems and that sigma ligands exert effects, which suggest antipsychotic potential.