FR-113680 - A NOVEL TRIPEPTIDE SUBSTANCE-P ANTAGONIST WITH NK1 RECEPTOR SELECTIVITY

1 We have discovered a novel tripeptide substance P (SP) antagonist, FR 113680 [N(alpha)-[N(alpha)-(N(alpha)-acetyl-L-threonyl)-N'-formyl-D-tryptophyl]-N-methyl-N-phenylmethyl-L-phenylalaninamide]. In binding experiments, FR 113680 inhibited [H-3]-SP binding to guinea-pig lung membranes (NK1) in a competitive manner but had not effect on [H-3]-SP binding to rat cerebral cortical membranes (NK1), [H-3]-neurokinin A ([H-3]-NKA) binding to rat duodenum smooth muscle membranes (NK2) and [H-3]-eledoisin (Ele) binding to rat cerebral cortical membranes (NK3). 2 In bioassay experiments, FR 113680 dose-dependently inhibited SP-induced guinea-pig ileum contraction (NK1), but did not inhibit either NKA-induced rat vas deferens contraction (NK2) or neurokinin B (NKB)-induced contraction of rat portal vein (NK3). According to Schild plot analysis, the inhibitory effect of FR 113680 on SP-induced guinea-pig ileum contraction is competitive and the pA2 value is 7.53. 3 The inactivity of FR 113680 on NK1 receptors in rat compared to guinea-pig may represent species-specific forms of the NK1 receptor. 4 These findings suggest that FR 113680 interacts selectively with the NK1 neurokinin receptor.