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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.