Motilin
/ Endogenous 22-residue gut peptide; motilin receptor (MLNR/GPR38) agonistALIAS · MLN
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Tier 3 for native motilin. The motilin receptor (MLNR / GPR38) is the molecular target of erythromycin and azithromycin used off-label as prokinetic agents - both macrolides act as motilin-receptor agonists at sub-antimicrobial doses. Synthetic motilin agonists (camicinal / GSK962040) reached Phase 2 in gastroparesis and were not advanced to approval.
Motilin is a 22-residue peptide secreted by M cells of the proximal small intestine. It is the primary humoral driver of the migrating motor complex (MMC) - the cyclic, fasting-state pattern of gastric and small-bowel contractions that sweeps undigested material distally between meals. Motilin levels rise cyclically every 90-120 minutes during fasting and trigger Phase III contractile activity.
The motilin receptor (MLNR, also known as GPR38) is a class A G-protein-coupled receptor expressed on enteric neurons and smooth muscle. Receptor activation drives acetylcholine release from enteric cholinergic motor neurons and promotes coordinated antral and duodenal contraction. The macrolide antibiotics erythromycin and azithromycin bind MLNR as agonists at concentrations well below their antimicrobial range, accounting for their well-known prokinetic effect.
Motilin and ghrelin receptors share substantial sequence homology and ligand cross-reactivity, with implications for combined-pathway prokinetic strategies.
No native motilin product is FDA-approved. Erythromycin and azithromycin are FDA-approved as antibiotics and used off-label as prokinetics by virtue of motilin-receptor agonism. Camicinal (GSK962040), a non-peptide motilin agonist, reached Phase 2 in diabetic gastroparesis with modest gastric-emptying signals that were not considered sufficient to advance to Phase 3.
Intravenous motilin is generally well tolerated in research settings; gastrointestinal cramping is the principal dose-limiting effect. Tachyphylaxis to motilin-receptor agonism is a notable feature of erythromycin's prokinetic use - the receptor downregulates with sustained exposure.
Regulatory status
- FDA status:
- Not FDA-approved
The motilin pathway is a paradigm of an attractive target with disappointing therapeutic translation - mechanistically clear, robust preclinical data, an approved-drug class with off-label proof-of-concept, yet no purpose-built motilin agonist has gained approval.
Vendor-sold motilin peptide is intended for research use only. There is no human pharmacokinetic data supporting self-administration of native motilin, and the receptor desensitisation phenomenon limits sustained-dosing utility even in principle.