PHARMACOLOGICAL PROFILES OF NEW ORALLY-ACTIVE NONPEPTIDE TACHYKININ NK1 RECEPTOR ANTAGONISTS

Pharmacological profiles of new orally active amide-based tachykinin N K1 receptor antagonists, N,7-dimethyl-8-oxo-1,7-naphthyridine-6-carbox amide (referred to as compound I) and two related compounds (compounds II and III), were compared with that of 2S,3S)-3-(2-methoxybenzylamin o)-2-phenylpiperidine (CP-99,994), another nonpeptide tachykinin NK1 r eceptor antagonist. Compounds I, II, III and CP-99,994 caused parallel rightward shifts of the concentration-response curve of substance P i n the guinea-pig ileum pretreated with atropine, mepyramine and indome thacin, with the pA(2) values of 8.70, 7.56, 8.41 and 8.27, respective ly. These antagonists did not alter the concentration-response curve o f acetylcholine in the guinea-pig ileum nor that of neurokinin A in th e rat vas deferens. Furthermore, contractile responses to senktide of the rat portal vein were not affected by these antagonists. In the iso lated neonatal gerbil spinal cord pretreated with tetrodotoxin, substa nce P produced a dose-dependent depolarization of ventral roots. Compo unds I, II, III and CP-99,994 caused parallel rightward shifts of the concentration-response curve of substance P in the spinal cord with th e pA(2) values of 7.07, 5.93, 6.40 and 7.26, respectively. In contrast , these antagonists did not affect the concentration-response curve of L-glutamate. These results suggest that compounds I, II and III are s elective antagonists for tachykinin NK1 receptor both in peripheral ti ssues and the central nervous system. (C) 1998 Elsevier Science B.V.