Vol. 298, Issue 2, 559-564, August 2001

Effects of TAK-637, a Novel Neurokinin-1 Receptor Antagonist, on Colonic Function in Vivo

Shiho Okano, Hideaki Nagaya, Yoshinori Ikeura, Hideaki Natsugari and Nobuhiro Inatomi

Pharmaceutical Discovery Research Division and Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan

Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In 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-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-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 agonist [pGlu⁶]SP_6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu⁶]SP_6-11-induced defecation, but did not significantly affect 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 peripheral -receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK₁ receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.