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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 559-564;
Shiho Okano
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Hideaki Nagaya
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Yoshinori Ikeura
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Hideaki Natsugari
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Nobuhiro Inatomi
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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]SP6–11significantly 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 κ-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.

Footnotes

  • Abbreviations:
    SP
    substance P
    NKA
    neurokinin A
    NKB
    neurokinin B
    NK1
    neurokinin-1
    IBS
    irritable bowel syndrome
    CRF
    corticotropin-releasing factor
    5-HT
    5-hydroxytryptamine
    ACTH
    adrenocorticotropic hormone
    • Received December 27, 2000.
    • Accepted April 14, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 559-564;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 559-564;
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