Motilin receptors (provisional nomenclature, [6]) are activated by a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide (MLN, P12872). These receptors are also suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin), although for many of these molecules the evidence is sparse.

In laboratory rodents, the gene encoding the motilin percursor appears to be absent, while the receptor appears to be a pseudogene. Functions of motilin (MLN, P12872) are not usually detected in rodents, although brain and other responses to motilin (MLN, P12872) and the macrolide ABT-229 have been reported and the mechanism of these actions are obscure [13-14].

* Key recommended reading is highlighted with an asterisk

* De Smet B, Mitselos A, Depoortere I. (2009) Motilin and ghrelin as prokinetic drug targets. Pharmacol. Ther., 123 (2): 207-23. [PMID:19427331]

* Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57: 279-288. [PMID:15914470]

Sanger GJ. (2008) Motilin, ghrelin and related neuropeptides as targets for the treatment of GI diseases. Drug Discov. Today, 13 (5-6): 234-9. [PMID:18342799]

* Sanger GJ, Wang Y, Hobson A, Broad J. (2012) Motilin: Toward a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists. Br. J. Pharmacol.,  [Epub ahead of print]. [PMID:23189978]

* Takeshita E, Matsuura B, Dong M, Miller LJ, Matsui H, Onji M. (2006) Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol, 41: 223-230. [PMID:16699856]

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2. 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 (3): 242-5. [PMID:10081621]

3. Coulie B, Matsuura B, Dong M, Hadac EM, Pinon DI, Feighner SD, Howard AD, Miller LJ. (2001) Identification of peptide ligand-binding domains within the human motilin receptor using photoaffinity labeling. J Biol Chem, 276: 35518-35522. [PMID:11461914]

4. Depoortere I, Peeters TL. (1995) Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle. Regul. Pept., 55 (3): 227-35. [PMID:7761622]

5. Feighner SD, Tan CP, McKee KK, Palyha OC, Hreniuk DL, Pong SS, Austin CP, Figueroa D, MacNeil D, Cascieri MA, Nargund R, Bakshi R, Abramovitz M, Stocco R, Kargman S, O'Neill G, Van der Ploeg LH, Evans J, Patchett AA, Smith RG, Howard AD. (1999) Receptor for motilin identified in the human gastrointestinal system. Science, 284: 2184-2188. [PMID:10381885]

6. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57: 279-288. [PMID:15914470]

7. Haramura M, Okamachi A, Tsuzuki K, Yogo K, Ikuta M, Kozono T, Takanashi H, Murayama E. (2002) Design and synthesis of motilin antagonists derived from the [1-4] fragment of porcine motilin. J. Med. Chem., 45 (3): 670-5. [PMID:11806718]

8. Koga H, Sato T, Tsuzuki K, Onoda H, Kuboniwa H, Takanashi H. (1994) Potent, acid-stable and orally active macrolide-type motilin receptor agonists, GM-611 and the derivatives. Bioorganic and Medicinal Chemistry Letters, 4 (11): 1347-1352.

9. Li JJ, Chao HG, Wang H, Tino JA, Lawrence RM, Ewing WR, Ma Z, Yan M, Slusarchyk D, Seethala R et al.. (2004) Discovery of a potent and novel motilin agonist. J. Med. Chem., 47 (7): 1704-8. [PMID:15027861]

10. Matsuura B, Dong M, Coulie B, Pinon DI, Miller LJ. (2005) Demonstration of a specific site of covalent labeling of the human motilin receptor using a biologically active photolabile motilin analog. J Pharmacol Exp Ther, 313: 1101-1108. [PMID:15677347]

11. Matsuura B, Dong M, Miller LJ. (2002) Differential determinants for peptide and non-peptidyl ligand binding to the motilin receptor. Critical role of second extracellular loop for peptide binding and action. J Biol Chem, 277: 9834-9839. [PMID:11781320]

12. Matsuura B, Dong M, Naik S, Miller LJ, Onji M. (2006) Differential contributions of motilin receptor extracellular domains for peptide and non-peptidyl agonist binding and activity. J Biol Chem, 281: 12390-12396. [PMID:16531413]

13. McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD, Van der Ploeg LH. (1997) Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics, 46: 426-434. [PMID:9441746]

14. Nieuwenhuijs VB, van Duijvenbode-Beumer H, Verheem A, Visser MR, Verhoef J, Gooszen HG, Akkermans LM. (1999) The effects of ABT-229 and octreotide on interdigestive small bowel motility, bacterial overgrowth and bacterial translocation in rats. Eur. J. Clin. Invest., 29 (1): 33-40. [PMID:10092986]

15. Sanger GJ, Westaway SM, Barnes AA, Macpherson DT, Muir AI, Jarvie EM, Bolton VN, Cellek S, Näslund E, Hellström PM et al.. (2009) GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurogastroenterol. Motil., 21 (6): 657-64, e30-1. [PMID:19374732]

16. Sudo H, Yoshida S, Ozaki K, Muramatsu H, Onoma M, Yogo K, Kamei K, Cynshi O, Kuromaru O, Peeters TL et al.. (2008) Oral administration of MA-2029, a novel selective and competitive motilin receptor antagonist, inhibits motilin-induced intestinal contractions and visceral pain in rabbits. Eur. J. Pharmacol., 581 (3): 296-305. [PMID:18164286]

17. 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 (2): 624-8. [PMID:7752063]

18. Takanashi H, Yogo K, Ozaki K, Koga H, Itoh Z, Omura S. (2007) In vitro pharmacological characterization of mitemcinal (GM-611), the first acid-resistant non-peptide motilin receptor agonist, in smooth muscle of rabbit small intestine. Pharmacology, 79 (3): 137-48. [PMID:17183187]

19. Thielemans L, Depoortere I, Perret J, Robberecht P, Liu Y, Thijs T, Carreras C, Burgeon E, Peeters TL. (2005) Desensitization of the human motilin receptor by motilides. J Pharmacol Exp Ther, 313: 1397-1405. [PMID:15764739]

20. Westaway SM, Brown SL, Fell SC, Johnson CN, MacPherson DT, Mitchell DJ, Myatt JW, Stanway SJ, Seal JT, Stemp G et al.. (2009) Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate. J. Med. Chem., 52 (4): 1180-9. [PMID:19191554]

21. Westaway SM, Sanger GJ. (2009) The identification of and rationale for drugs which act at the motilin receptor. Prog Med Chem, 48: 31-80. [PMID:21544957]

22. Zhao DM, Xue HH, Chida K, Suda T, Oki Y, Kanai M, Uchida C, Ichiyama A, Nakamura H. (2000) Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells. Am. J. Physiol. Lung Cell Mol. Physiol., 278 (4): L726-36. [PMID:10749750]

Subcommittee members: Anthony P. Davenport (Chairperson) Clinical Pharmacology Unit University of Cambridge Level 6, Centre for Clinical Investigation Box 110, Addenbrooke's Hospital Cambridge, CB2 2QQ UK