alemcinal and mitemcinal

The pharmacological properties of mitemcinal (GM-611), the first acid-resistant non-peptide motilin agonist, were investigated in the smooth muscle of the rabbit small intestine and compared with porcine motilin (pMTL), erythromycin A (EMA) and its derivatives (EM-523, EM-574 and ABT-229). Mitemcinal, pMTL, EMA, EM-523, EM-574 and ABT-229 produced concentration-dependent contractions with approximately the same maximum contractions in the isolated rabbit duodenum longitudinal strips. The contractile response to mitemcinal or pMTL was competitively inhibited by a selective motilin antagonist, GM-109. The pA(2) values for GM-109 as an antagonist of mitemcinal and pMTL showed approximately the same values. However, the concentration-dependent contractile responses to mitemcinal or pMTL were not affected by pretreatment with atropine, tetrodotoxin, hexamethonium, naloxone or tropisetron. The removal of calcium ions from the medium and pretreatment with verapamil greatly suppressed the contractions induced by mitemcinal and pMTL. The contractile response to mitemcinal was not affected by preincubation in acidic solutions, while those of EM-523, EM-574 and ABT-229 were strongly diminished in the same condition. Mitemcinal as well as other motilin agonists displaced (125)I-pMTL bound to a homogenate of the rabbit duodenum muscle tissue. The displacement curves of all these compounds were parallel. These results indicate that mitemcinal is a selective and full motilin receptor agonist in the smooth muscle of the rabbit small intestine and that this agent has an excellent acid-resistant property.

Topics: Acetylcholine; Animals; Atropine; Binding, Competitive; Calcium Chloride; Diltiazem; Dose-Response Relationship, Drug; Erythromycin; Hexamethonium; Hydrogen-Ion Concentration; In Vitro Techniques; Indoles; Intestine, Small; Male; Molecular Structure; Muscle Contraction; Muscle, Smooth; Naloxone; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Tetrodotoxin; Tropisetron; Verapamil

1. The present study was undertaken to determine whether the macrolide antibiotic erythromycin, its stable motilide derivatives ABT 229 and GM 611 and motilin act at the same receptors on intestinal muscle 2. Each compound contracted the longitudinal muscle of the rabbit duodenum in a concentration-dependent manner that was unaffected by 1 mumol/L tetrodotoxin. The potency order (pEC50 values in brackets) was motilin (8.4), ABT 229 (7.6), GM 611 (7.5) and erythromycin (6.0). 3. The motilin receptor antagonists GM 109 and [phe3, leu13]-motilin, both shifted the concentration-response curves for each agonist to the right, but did not affect concentration-response relationships for the muscarinic agonist carbachol. Schild regression analysis yielded similar pA2 values for GM 109 (in the range 7.2-7.5) for all agonists. This analysis was not done for [phe3, leu13]motilin, which was a non-competitive antagonist and partial agonist. 4. It is concluded that erythromycin, the motilides and motilin act at the same (motilin) receptor on rabbit duodenal muscle and do not have any detectable actions at other receptors in this preparation.

Topics: Animals; Anti-Bacterial Agents; Carbachol; Dose-Response Relationship, Drug; Duodenum; Erythromycin; Female; Gastrointestinal Agents; Male; Motilin; Muscle Contraction; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide