Effects of TAK-480, a Novel Tachykinin NK2–Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid–Induced Defecation in Guinea Pigs

Abstract

TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK2–receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK2 receptors with a marked species difference and a 10,000-fold selectivity versus NK1 and NK3 receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK2 receptor–selective agonist beta-Ala8-NKA(4-10) (βA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT3–receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid–induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as βA-NKA in an isolated human colon. In conclusion, the novel NK2-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK2 receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.