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Ghrelin and motilin receptors as drug targets for gastrointestinal disorders

Key Points

  • Ghrelin and motilin are related hormones found in the stomach and small intestine

  • Each has roles in relation to the feeding cycle

  • Both the ghrelin and motilin receptor have been investigated as therapeutic targets for digestive disorders, but no compounds with selective activity are yet in clinical use

  • Ligand-dependent differences in receptor function (biased agonism) and constitutive activity of the ghrelin receptor have contributed to previous drug discovery difficulties, but offer new approaches for drug design

  • The most promising targets for use of ghrelin receptor agonists are in the treatment of constipation and in patients requiring increased appetite and reduced nausea

  • The most promising targets for use of motilin receptor agonists are gastroparesis and disorders in which gastric emptying needs to be increased (for example, during enteral feeding)

Abstract

The gastrointestinal tract is the major source of the related hormones ghrelin and motilin, which act on structurally similar G protein-coupled receptors. Nevertheless, selective receptor agonists are available. The primary roles of endogenous ghrelin and motilin in the digestive system are to increase appetite or hedonic eating (ghrelin) and initiate phase III of gastric migrating myoelectric complexes (motilin). Ghrelin and motilin also both inhibit nausea. In clinical trials, the motilin receptor agonist camicinal increased gastric emptying, but at lower doses reduced gastroparesis symptoms and improved appetite. Ghrelin receptor agonists have been trialled for the treatment of diabetic gastroparesis because of their ability to increase gastric emptying, but with mixed results; however, relamorelin, a ghrelin agonist, reduced nausea and vomiting in patients with this disorder. Treatment of postoperative ileus with a ghrelin receptor agonist proved unsuccessful. Centrally penetrant ghrelin receptor agonists stimulate defecation in animals and humans, although ghrelin itself does not seem to control colorectal function. Thus, the most promising uses of motilin receptor agonists are the treatment of gastroparesis or conditions with slow gastric emptying, and ghrelin receptor agonists hold potential for the reduction of nausea and vomiting, and the treatment of constipation. Therapeutic, gastrointestinal roles for receptor antagonists or inverse agonists have not been identified.

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Figure 1: Ghrelin, motilin and their receptors.
Figure 2: Major pathways used by endogenous ghrelin and motilin to modulate upper gastrointestinal function.
Figure 3: The site of action of ghrelin receptor (GHSR1a) ligands in the defecation control pathway.

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Acknowledgements

Work from the Queen Mary University of London laboratory is currently supported by the research into ageing fund, set up and managed by AgeUK, British Biotechnology Science Research Council, Dunhill Medical Trust, and Takeda Pharmaceuticals. Work from the University of Melbourne laboratory is supported by the National Health and Medical Research Council of Australia (project grant number 1079739) and the Transport Accident Commission, through the Institute for Safety, Compensation and Recovery Research.

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Correspondence to Gareth J. Sanger.

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G.J.S. is currently in receipt of a student CASE award from the British Biotechnology Science Research Council, sponsored by GlaxoSmithKline, and receives research funding from Takeda Pharmaceuticals. He has previously received funding from GlaxoSmithKline and RaQualia. J.B.F. declares no competing interests.

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Sanger, G., Furness, J. Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol 13, 38–48 (2016). https://doi.org/10.1038/nrgastro.2015.163

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