NEUROPHARMACOLOGICAL CHARACTERIZATION OF SR-140333, A NON PEPTIDE ANTAGONIST OF NK1 RECEPTORS

SR 140333 -yl]ethyl}-4-phenyl-1-azonia-bicyclo[2.2.2]octane, chloride) , a potent non peptide ligand of the substance P (SP) NK1 receptor sub type with high affinity for NK1 receptors from both rat cortical membr anes and human IM9 cells (K-i=0.02 nM and 0.01 nM, respectively) was s tudied in vivo on various effects induced by NK1 agonists in rats and mice. SR 140333 given intraperitoneally (i.p.) in mice antagonized dos e-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 intrastriat al SP and septide (ID50=0.07 and 0.06 mg/kg, respectively). This compo und had little effect on the scratching responses and the turning beha vior elicited by [Sar(9), Met(O-2)(11)]-SP. When SR 140333 was coadmin istered with the peptide agonist, the compound reduced the scratching responses elicited by SP, [Sar(9), Met(O-2)(11)]-SP and septide inject ed intrathecally (i.t.) in mice (ID50=72.0, 64.3 and 52.5 ng i.t., res pectively). SR 140333 antagonized the salivation induced by SP, [Sar(9 ), Met(O-2)(11)]-SP and septide in rats (ID50=0.13, 0.18 and 0.09 mg/k g i.p., respectively). SR 140333 abolished the facilitation of the tai l-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 beh avior 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.