EM574, AN ERYTHROMYCIN DERIVATIVE, IS A MOTILIN RECEPTOR AGONIST IN THE RABBIT

This study was performed to examine whether an erythromycin derivative , de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (E M574) is a motilin receptor agonist in the rabbit gastrointestinal tra ct. EM574 and porcine motilin induced contractions in segments of isol ated rabbit intestine with pEC(50) values of 8.26 +/- 0.04 and 8.69 +/ - 0.07, respectively, but not in rat or guinea pig preparations, The s ensitivity and efficacy of the response to both compounds in rabbits d ecreased aborally and was insensitive to pretreatment with atropine or tetrodotoxin, but was markedly suppressed under Ca2+-free conditions. EM574 and porcine motilin specifically displaced [I-125-Tyr(23)]canin e motilin bound to gastric antral smooth muscle homogenates with pIC(5 0) values of 8.21 +/- 0.13 and 9.20 +/- 0.11, respectively. The pEC(50 ) value for the contractile response and pIC(50) value for the recepto r binding for motilin, EM574, erythromycin A and three other derivativ es correlated well (r = 0.94, P < 0.01). Tissue section autoradiograph y in the antrum revealed that specific labeled motilin binding sites w ere localized in the circular muscle layer and myenteric plexus, and c ould be reduced in the presence of an excess of EM574. These results i ndicate that EM574 is a potent motilin receptor agonist in the rabbit gastrointestinal tract. (C) 1997 Elsevier Science B.V.