title: Antagonistic properties of [Phe3,Leu13]porcine motilin.
abstract: We describe the antagonistic properties due to the replacement of Pro3 by phenylalanine in porcine motilin. The analogue, [Phe3,Leu13] porcine motilin (OHM-11526), displaces iodinated [Nle13]porcine motilin bound to a homogenate of rabbit antral smooth muscle tissue. The dissociation constant (pKd) was 9.26 +/- 0.04, versus 9.11 +/- 0.01 for motilin and 8.24 +/- 0.06 for ANQ-11125, the (1-14) fragment of OHM-11526. The Hill coefficient was close to one and Schild plot analysis confirmed the competitive nature of the interaction. In the tissue bath OHM-11526 was unable to induce contractions of segments of rabbit duodenum. At a concentration of 10(-6) M, OHM-11526 was unable to induce contractions of segments of rabbit duodenum. At a concentration of 10(-6) M, OHM-11526 inhibited the effect of maximally effective doses of porcine motilin and of the erythromycin derivative, EM-523, but was without effect on contractions induced by acetylcholine, substance P and serotonin. Increasing doses of OHM-11526 shifted the dose-response curves of motilin and EM-523 to the right, but caused a depression of the maximal response as well. From the motilin curves, and assuming a dual competitive and non-competitive interaction, the pA2 was 7.79 +/- 0.08, the pD'2 6.91 +/- 0.08. The EM-523 curves yielded comparable data (pA2 = 8.10 +/- 0.12 and pD'2 = 7.06 +/- 0.13). OHM-11526 also blocked the motilin responses observed with smooth muscle strips from the rabbit and human antrum. However, in a preparation of the chicken small intestine, OHM-11526 was a full agonist with a potency (pD2 = 6.84) comparable to that of porcine motilin (pD2 = 6.71). Our data confirm the interaction of motilides with the motilin receptor. Due to its increased affinity for the motilin receptor, OHM-11526 will be a valuable took for studying the physiology of motilin and the pharmacology of motilin and motilides.
authors.affiliation: Department of Pathophysiology, Katholieke Universiteit Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Depoortere
authors.forename: M J
authors.initials: MJ
authors.lastname: Macielag
authors.forename: A
authors.initials: A
authors.lastname: Galdes
authors.forename: T L
authors.initials: TL
authors.lastname: Peeters
mesh_terms: D000818:Animals; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D009037:Motilin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
chemical_list: C099047:OHM 11526; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; C085546:ANQ 11125; D009037:Motilin