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. 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]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6-11-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 kappa-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.
Okano
S
S
Pharmaceutical Discovery Research Division and Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Nagaya
H
H
Ikeura
Y
Y
Natsugari
H
H
Inatomi
N
N
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D003106:Colon / Q000187:drug effects*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003672:Defecation / Q000187:drug effects; D003714:Denervation; D005849:Gerbillinae; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology*; D015288:Neurokinin A / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000502:physiology; D012149:Restraint, Physical; D012701:Serotonin / Q000494:pharmacology; D013315:Stress, Psychological / Q000097:blood / Q000523:psychology; D013373:Substance P / Q000494:pharmacology / Q000502:physiology
D018721:Muscarinic Agonists; D009287:Naphthyridines; D064729:Neurokinin-1 Receptor Antagonists; D012701:Serotonin; D013373:Substance P; D015288:Neurokinin A; D002217:Carbachol; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; C403052:TAK 637