1. Erythromycin lactobionate caused a concentration-dependent inhibition of nerve-mediated contractions of the longitudinal muscle of the guinea-pig ileum, with a threshold for effect of 10-30 mumol/L. The non-antibiotic derivative of erythromycin ABT-229 had a similar effect, but was approximately 10-fold less potent. At a greater concentration (1 mmol/L), erythromycin also depressed the direct contractile effect of 10 mumol/L carbachol on the muscle. 2. Human/porcine motilin (up to 100 mumol/L) did not reduce the nerve-mediated contractions, although it did contract the muscle (threshold 30 mumol/L). Antagonists of motilin receptors (phe3leu13motilin, up to 1 mumol/L, and GM-109, up to 3 mumol/L) did not reduce responses to erythromycin. 3. Erythromycin contracted the longitudinal muscle of the rabbit duodenum, with a threshold concentration of 0.1 mumol/L and ABT-229 contracted this tissue at a threshold concentration of 0.01 mumol/L. Effects of both agonists were antagonized by the motilin receptor antagonists phe3leu13motilin (0.3 mumol/L) and GM-109 (1 mumol/L). 4. It is concluded that the site(s) at which erythromycin acts in the guinea-pig ileum is not a motilin receptor and that ABT-229 is selective for the motilin receptor in comparison with non-motilin erythromycin sites and is unlikely to act at the latter site in therapeutic doses.

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.