Motilin receptors

Pharmacodynamics What the drug does to the patient. For example, erythromycin stimulates gut motilin receptors and may induce nausea. The patient may stop taking the erythromycin. 

In addition to these receptors, enkephalins may be involved in some parts of this process, while agents which act on gastric serotonin (5-HT4), dopamine, and motilin receptors accelerate gastric emptying and relieve symptoms in gastroparesis. 

Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Intravenous erythromycin (3 mg/kg) is beneficial in some patients with gastroparesis however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy. 

Erythromycin motilide, (II), and furan erythromycin motilide derivatives, (III), prepared by Santi (2) and Ashley (3), respectively, were effective as motilin receptor agonists and used in treating conditions associated with impaired gastric motility. 

Cyclobutene, (IV), and cyclopentene derivatives prepared by Chen (4,5), respectively, were effective as both motilin receptor antagonists and contractile smooth muscle antagonists and used in treating irritable bowel syndrome disorder. 

Cyclic motilin receptor antagonists, (V), prepared by Matsuoka (6) were effective in treating irritable bowel syndrome in patients showing diarrhea or hypermotilinemia conditions. 

Motilin Motilin receptor 22-residue peptide Stimulate migrating motor complex Solid-phase V"-Boc chemistry... 

Gastrointestinal symptoms were the most common adverse effects reported in a trial of azithromycin in disseminated Mycobacterium avium complex in 62 patients with AIDS (30). Erythromycin is a motilin receptor agonist (31-33). This mechanism may be at least partly responsible for the gastrointestinal adverse effects of macrolides. Azithromycin may act on gastrointestinal motility in a similar way to erythromycin, as it produces a significant increase in postprandial antral motility (34). 

Hasler WL, Heldsinger A, Chung OY. Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors. Am J Physiol 1992 262(1 Pt l) G50-5. 

Erythromycin is a motilin receptor agonist (2-4). Azithromycin also produced a significant increase in postprandial antral motility (5). Clarithromycin is also prokinetic, as shown in 16 patients with functional dyspepsia and Helicobacter pylori gastritis (6). For this reason, the macrolides have been used to treat gastroparesis (7). 

Adverse reactions Erythromycin can cause nausea, vomiting, diarrhea, and abdominal cramping. Gl intolerance due to erythromycin is due to direct stimulation of the motilin receptor, leading to increased Gl motility. This occurs with both the IV and PO formulation. Although rare, all macrolides can cause hepatotoxicity. The estolate formulation of erythromycin has been associated with cholestatic hepatitis in pregnant women. In high doses, all macrolides can cause tinnitus. All macrolides can cause QT prolongation and torsade de points... 

The motilides interact with motilin receptors on gastrointestinal neurons and smooth muscle, stimulating smooth muscle contraction and... 

Other macrolide antimicrobials, such as clarithromycin and azithromycin, appear to interact with motilin receptors. Current investigations center on developing motilides that lack antimicrobial activity, thus not disrupting the normal intestinal flora, but have more potent effects on motility. Isolation and purification of motilin receptors will facilitate the development of drugs that have highly specific motilide activity. 

One of the most impressive synthetic achievements with the P-based mediators is the deoxygenation of an erythromycin B derivative towards the industrial synthesis of ABT-229, a potent motilin receptor agonist. Clean... 

From the perspective of structure-activity relationships, it is interesting that both motilin and motilides act as agonists for the motilin receptor, even though they have very different chemical structures (Fig. 17). Studies on the structure-activity relationship of motilin revealed that four hydrophobic residues, Phe 1, Val 2, He 4, and Tyr 7, of the motilin N-terminal region are most essential for its activity [38-41]. 

Satoh, M., Sakai, X, Sano, I., Fujikura, K., Kayama, H., Oshima, K., Itoh, Z and Omura, S. (1994). EM-574, an erythromycin derivative, is a potent motilin receptor agonist in human gastric antrum. J. Pharmacol. Exp. Then 271, 574-579. 

Bormans, V., Peeters, T. L., and Vantrappen, G. (1986). Motilin receptors in rabbit stomach and small intestine. Regul. Pept. 15, 143-153. 

Macrolides stimulate motilin receptors and cause gastrointestinal distress (erythromycin, azithromycin > clarithromycin)... 

Motilin receptor Induction of GI motility, GI cramps, diarrhea in some patients. This is difficult to distinguish from effects on GI flora. Stimulation of motilin receptor is also thought to be associated with increased downward peristalsis leading to a reduction in gastroesophageal reflux and reductions in aspiration of GI fluids into the bronchi. 25... 

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