Skip to main content

Effects of Motilin and Mitemcinal (GM-611) on Gastrointestinal Contractile Activity in Rhesus Monkeys In Vivo and In Vitro

Digestive Diseases and Sciences volume 52, pages 3112–3122 (2007)Cite this article

Abstract

Neither the presence of motilin receptors nor their action has been investigated in monkeys. The object of this study was to determine the effects of motilin and mitemcinal (GM-611), an erythromycin derivative, on the gastrointestinal tract in rhesus monkeys in vivo and in vitro. In in vivo investigations in conscious monkeys, both motilin and mitemcinal induced migrating motor complex-like contractions in the interdigestive state and also accelerated gastric emptying. In in vitro investigations, the presence of motilin receptors in the gastrointestinal tract was demonstrated by receptor binding assays. Motilin and mitemcinal contracted isolated duodenum strips in a concentration-dependent manner. In conclusion, rhesus monkeys may be useful for studying the physiological and pharmacological roles of the motilin agonistic mechanism because they show reactivity to motilin both in vivo and in vitro.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Brown JC, Mutt V, Dryburgh JR (1971) The further purification of motilin, a gastric motor activity stimulating polypeptide from the mucosa of the small intestine of hogs. Can J Physiol Pharmacol 49:399–405

    PubMed  CAS  Google Scholar 

  2. Itoh Z (1997) Motilin and clinical application. Peptides 18:593–608

    PubMed  Article  CAS  Google Scholar 

  3. Strunz U, Domschke W, Domschke S, Mitznegg P, Wunsch E, Jaeger E, Demling L (1976) Gastroduodenal motor response to natural motilin and synthetic position 13-substituted motilin analogues: a comparative in vitro study. Scand J Gastroenterol 11:199–203

    PubMed  CAS  Google Scholar 

  4. Strunz U, Domschke W, Mitznegg P, Domschke S, Schubert E, Wunsch E, Jaeger E, Demling L (1975) Analysis of the motor effects of 13-norleucine motilin on the rabbit, guinea pig, rat, and human alimentary tract in vitro. Gastroenterology 68:1485–1491

    PubMed  CAS  Google Scholar 

  5. Bormans V, Peeters TL, Vantrappen G (1986) Motilin receptors in rabbit stomach and small intestine. Regul Pept 15:143–153

    PubMed  Article  CAS  Google Scholar 

  6. Peeters TL, Bormans V, Vantrappen G (1988) Comparison of motilin binding to crude homogenates of human and canine gastrointestinal smooth muscle tissue. Regul Pept 23:171–182

    PubMed  Article  CAS  Google Scholar 

  7. Itoh Z, Honda R, Hiwatashi K, Takeuchi S, Aizawa I, Takayanagi R, Couch EF (1976) Motilin-induced mechanical activity in the canine alimentary tract. Scand J Gastroenterol Suppl 39:93–110

    PubMed  CAS  Google Scholar 

  8. Vantrappen G, Janssens J, Peeters TL, Bloom SR, Christofides ND, Hellemans J (1979) Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci 24:497–500

    PubMed  Article  CAS  Google Scholar 

  9. Guerrero-Lindner E, Arruebo MP, Murillo MD, Plaza MA (1996) Effect of motilin on gastrointestinal myoelectric activity in conscious rabbits. Peptides 17:901–907

    PubMed  Article  CAS  Google Scholar 

  10. Yoshida N, Mizumoto A, Iwanaga Y, Itoh Z (1991) Effects of 5-hydroxytryptamine 3 receptor antagonists on gastrointestinal motor activity in conscious dogs. J Pharmacol Exp Ther 256:272–278

    PubMed  CAS  Google Scholar 

  11. Haga N, Mizumoto A, Satoh M, Mochiki E, Mizusawa F, Ohshima K, Itoh Z (1996) Role of endogenous 5-hydroxytryptamine in the regulation of gastric contractions by motilin in dogs. Am J Physiol 270:G20–G28

    PubMed  CAS  Google Scholar 

  12. Leslie RA (1986) Comparative aspects of the area postrema: fine-structural considerations help to determine its function. Cell Mol Neurobiol 6:95–120

    PubMed  Article  CAS  Google Scholar 

  13. Poitras P, Lahaie RG, St-Pierre S, Trudel L (1987) Comparative stimulation of motilin duodenal receptor by porcine or canine motilin. Gastroenterology 92:658–662

    PubMed  CAS  Google Scholar 

  14. Mizumoto A, Sano I, Matsunaga Y, Yamamoto O, Itoh Z, Ohshima K (1993) Mechanism of motilin-induced contractions in isolated perfused canine stomach. Gastroenterology 105:425–432

    PubMed  CAS  Google Scholar 

  15. Itoh Z, Nakaya M, Suzuki T, Arai H, Wakabayashi K (1984) Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in the dog. Am J Physiol 247:G688–G694

    PubMed  CAS  Google Scholar 

  16. Peeters TL (1993) Erythromycin and other macrolides as prokinetic agents. Gastroenterology 105:1886–1899

    PubMed  CAS  Google Scholar 

  17. Ōmura S, Tsuzuki K, Sunazuka T, Marui S, Toyoda H, Inatomi N, Itoh Z (1987) Macrolides with gastrointestinal motor stimulating activity. J Med Chem 30:1941–1943

    PubMed  Article  Google Scholar 

  18. Tsuzuki K, Sunazuka T, Marui S, Toyoda H, Ōmura S, Inatomi N, Itoh Z (1989) Motilides, macrolides with gastrointestinal motor stimulating activity. I. O-Substituted and tertiary N-substituted derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal. Chem Pharm Bull (Tokyo) 37:2687–2700

    CAS  Google Scholar 

  19. Li JJ, Chao HG, Wang H, Tino JA, Lawrence RM, Ewing WR, Ma Z, Yan M, Slusarchyk D, Seethala R, Sun H, Li D, Burford NT, Stoffel RH, Salyan ME, Li CY, Witkus M, Zhao N, Rich A, Gordon DA (2004) Discovery of a potent and novel motilin agonist. J Med Chem 47:1704–1708

    PubMed  Article  CAS  Google Scholar 

  20. Huang Z, De Clercq P, Depoortere I, Peeters TL (1998) Isolation and sequence of cDNA encoding the motilin precursor from monkey intestine. Demonstration of the motilin precursor in the monkey brain. FEBS Lett 435:149–152

    PubMed  Article  CAS  Google Scholar 

  21. Peeters TL (2001) GM-611 (Chugai Pharmaceutical). Curr Opin Invest Drugs 2:555–557

    CAS  Google Scholar 

  22. Takanashi H, Yogo K, Ozaki K, Koga H, Itoh Z, Ōmura S (2007) In vitro pharmacological characterization of mitemcinal (GM-611), the first acid-resistant nonpeptide motilin receptor agonist, in smooth muscle of rabbit small intestine. Pharmacology (in press)

  23. McCallum RW, Fogel R, Fang JC, Altman RS, Faichney JD, Goldstein BJ (2005) Mitemcinal fumarate (GM-611) provided symptomatic relief of diabetic gastroparesis, especially in Type 1 diabetes: results of a 12-week, multi-center, double-blind, placebo-controlled, randomized phase 2b study (GM-611-05). Gastroenterology 128:A467

    Google Scholar 

  24. McCallum RW, Goldstein BJ (2006) Diabetic gastroparesis: effect of mitemcinal by subgroup analysis in a 12-week, randomized, multi-center, double-blind, placebo-controlled, phase 2b study. Gastroenterology 130:A598

    Google Scholar 

  25. Inatomi N, Satoh H, Maki Y, Hashimoto N, Itoh Z, Ōmura S (1989) An erythromycin derivative, EM-523, induces motilin-like gastrointestinal motility in dogs. J Pharmacol Exp Ther 251:707–712

    PubMed  CAS  Google Scholar 

  26. Takanashi H, Yogo K, Ozaki K, Ikuta M, Akima M, Koga H, Nabata H (1995) GM-109: a novel, selective motilin receptor antagonist in the smooth muscle of the rabbit small intestine. J Pharmacol Exp Ther 273:624–628

    PubMed  CAS  Google Scholar 

  27. Heading RC, Nimmo J, Prescott LF, Tothill P (1973) The dependence of paracetamol absorption on the rate of gastric emptying. Br J Pharmacol 47:415–421

    PubMed  CAS  Google Scholar 

  28. Tomomasa T, Kuroume T, Arai H, Wakabayashi K, Itoh Z (1986) Erythromycin induces migrating motor complex in human gastrointestinal tract. Dig Dis Sci 31:157–161

    PubMed  Article  CAS  Google Scholar 

  29. Boivin M, Pinelo LR, St-Pierre S, Poitras P (1997) Neural mediation of the motilin motor effect on the human antrum. Am J Physiol 272:G71–G76

    PubMed  CAS  Google Scholar 

  30. Miller P, Roy A, St-Pierre S, Dagenais M, Lapointe R, Poitras P (2000) Motilin receptors in the human antrum. Am J Physiol 278:G18–G23

    CAS  Google Scholar 

  31. Miller P, Trudel L, St-Pierre S, Takanashi H, Poitras P (2000) Neural and muscular receptors for motilin in the rabbit colon. Peptides 21:283–287

    PubMed  Article  CAS  Google Scholar 

  32. Van Assche G, Depoortere I, Thijs T, Janssens JJ, Peeters TL (1997) Concentration-dependent stimulation of cholinergic motor nerves or smooth muscle by [Nle13]motilin in the isolated rabbit gastric antrum. Eur J Pharmacol 337:267–274

    PubMed  Article  CAS  Google Scholar 

  33. Tanaka T, Mizumoto A, Mochiki E, Suzuki H, Itoh Z, Ōmura S (1998) Effects of EM574 and cisapride on gastric contractile and emptying activity in normal and drug-induced gastroparesis in dogs. J Pharmacol Exp Ther 287:712–719

    PubMed  CAS  Google Scholar 

  34. Depoortere I, Peeters TL, Vantrappen G (1993) Distribution and characterization of motilin receptors in the cat. Peptides 14:1153–1157

    PubMed  Article  CAS  Google Scholar 

  35. Depoortere I, Peeters TL, Vantrappen G (1991) Motilin receptors of the rabbit colon. Peptides 12:89–94

    PubMed  Article  CAS  Google Scholar 

  36. Depoortere I, Peeters TL, Vantrappen G (1990) The erythromycin derivative EM-523 is a potent motilin agonist in man and in rabbit. Peptides 11:515–519

    PubMed  Article  CAS  Google Scholar 

  37. Clark MJ, Wright T, Bertrand PP, Bornstein JC, Jenkinson KM, Verlinden M, Furness JB (1999) Erythromycin derivatives ABT 229 and GM 611 act on motilin receptors in the rabbit duodenum. Clin Exp Pharmacol Physiol 26:242–245

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Mr. Toyokazu Matsu-ura, Mr. Hajime Sano, Ms. Akiko Hiura, Ms. Mayumi Miyaguchi, and Ms. Yuriko Seto-Ozaki for their expert assistance in the animal experiments. The authors also thank Dr. Paul Langman and Mr. Geoffrey Read for their editorial assistance.

Author information

Affiliations

  1. Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, 412-8513, Japan

    Kenji Yogo, Ken-ichi Ozaki, Hisanori Takanashi & Masao Koto

  2. Gunma University, Maebashi, Gunma, 371-8512, Japan

    Zen Itoh

  3. The Kitasato Institute, Minato-ku, Tokyo, 108-8642, Japan

    Satoshi Ōmura

  4. Targeted Disease Areas Department, Chugai Pharmaceutical Co., Ltd., 1-1 Nihonbashi-Muromachi 2-Chome, Chuo-ku, Tokyo, 103-8324, Japan

    Hisanori Takanashi

Authors
  1. Kenji Yogo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ken-ichi Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hisanori Takanashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masao Koto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zen Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Ōmura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hisanori Takanashi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yogo, K., Ozaki, Ki., Takanashi, H. et al. Effects of Motilin and Mitemcinal (GM-611) on Gastrointestinal Contractile Activity in Rhesus Monkeys In Vivo and In Vitro. Dig Dis Sci 52, 3112–3122 (2007). https://doi.org/10.1007/s10620-006-9672-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-006-9672-5

Key words

  • Motilin
  • Mitemcinal
  • GM-611
  • Rhesus monkey
  • Gastrointestinal motility
  • Gastric emptying
  • Motilin receptor