Effects of TAK-637, a novel neurokinin-1 receptor antagonist, on colonic function in vivo

Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. I n this study, we investigated the effect of SP on colonic function and the effect of TAK-637 {(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tet rahydro-9-methyl-5-(4- methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyri dine-6,13-dione}, a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 ag onist [pGlu(6)]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu(6)]SP6-11,-induced defecation, but did not significantly affe ct neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the periphe ral kappa -receptor agonist trimebutine, also reduced restraint stress-stim ulated defecation. TAK-637 inhibited the increase in fecal pellet output st imulated by intracerebroventricular injection of corticotropin-releasing fa ctor, but did not affect the stress-induced increase in plasma adrenocortic otropic hormone levels. Denervation of the sensory neurons with capsaicin d id not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced ch anges in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.