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 alemcinal 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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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]

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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