SUBSTANCE-P (NK-1 RECEPTOR) ANTAGONISTS - INVIVO AND INVITRO ACTIVITIES IN RATS AND GUINEA-PIGS

NK-I receptor subtypes have been identified by the use of CP-96,345 and RP-67, 580, two non-peptide antagonists. These and other antagonists have been tested in vivo and in vitro in guinea pigs and rats to counteract the hypotensive and contractile (urinary isolated bladder) effects of a) SP, b) the NK-1 selective agonist [Sar9,Met(O2)11]SP and c) other neurokinins. CP-96,345 has been found to be more active on the guinea pig and RP-67,580 more active on the rat by at least 1 log unit both in vivo and in vitro. Both compounds are selective NK-1 antagonists and RP-67,580 appears to be weaker than CP-96,345. Two in vitro preparations, the guinea pig and rat urinary bladder are proposed as bioasssays for the NK-1, (guinea pig) and NK-1, (rat) receptor subtypes, which have been shown to mediate smooth muscle contraction and hypotension, resulting from peripheral vasodilatation. CP-96,345 and RP-67,580 are more potent antagonists than spantide, its homologous octapeptide and the Fujisawa tri or dipeptides.