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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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]

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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]

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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]

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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]

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