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

Abstract

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.

• Authors: S Okano, H Nagaya, Y Ikeura, H Natsugari, N Inatomi
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 298 Issue 2 Pg. 559-64 (Aug 2001) ISSN: 0022-3565 [Print] United States
• PMID: 11454917 (Publication Type: Journal Article)

Chemical References

• Muscarinic Agonists
• Naphthyridines
• Neurokinin-1 Receptor Antagonists
• Serotonin
• Substance P
• Neurokinin A
• Carbachol
• Adrenocorticotropic Hormone
• Corticotropin-Releasing Hormone
• TAK 637

Topics

• Adrenocorticotropic Hormone (blood)
• Animals
• Carbachol (pharmacology)
• Colon (drug effects)
• Corticotropin-Releasing Hormone (pharmacology)
• Defecation (drug effects)
• Denervation
• Gerbillinae
• Male
• Muscarinic Agonists (pharmacology)
• Naphthyridines (pharmacology)
• Neurokinin A (pharmacology)
• Neurokinin-1 Receptor Antagonists
• Neurons, Afferent (physiology)
• Restraint, Physical
• Serotonin (pharmacology)
• Stress, Psychological (blood, psychology)
• Substance P (pharmacology, physiology)