Motilin

Motilin is a 22-amino acid peptide hormone produced by endocrine Mo-cells in the duodenum and jejunum. Discovered in 1971 by John Brown and colleagues, motilin plays a unique role in gastrointestinal physiology as the primary hormonal regulator of the migrating motor complex (MMC), the cyclical pattern of electrical and motor activity that sweeps through the stomach and small intestine during the fasting state.

The MMC consists of four phases, with Phase III being the most vigorous — characterized by strong coordinated contractions that move undigested material, cellular debris, and bacteria from the stomach through the small intestine. Motilin release follows a cyclical pattern occurring approximately every 90-120 minutes during fasting, and its peaks coincide with Phase III of the MMC. This "housekeeping" function is essential for maintaining gut health, preventing bacterial overgrowth, and clearing residual material between meals.

Motilin acts through the motilin receptor, a G-protein coupled receptor expressed on smooth muscle cells and enteric neurons of the gastrointestinal tract. Activation of this receptor triggers the strong contractile activity associated with Phase III of the MMC. Notably, the macrolide antibiotic erythromycin is a motilin receptor agonist, which explains its well-known side effect of stimulating gastrointestinal motility and also its therapeutic use as a prokinetic agent.

The relationship between erythromycin and the motilin receptor has driven pharmaceutical interest in developing motilinergic prokinetic drugs for gastroparesis and other motility disorders. Several motilin receptor agonists (motilides) have been investigated, including camicinal and mitemcinal, though none have yet achieved widespread regulatory approval. The challenge has been developing compounds that maintain prokinetic efficacy without the antibiotic activity of erythromycin and without inducing tachyphylaxis (rapid tolerance).