title: Analysis of neurogenic contractions induced by ML-1035 and other benzamides in the guinea-pig non-stimulated isolated ileum.
abstract: 4-Amino-5-chloro-substituted benzamides have been shown to increase gastric motility in-vivo and enhance field-stimulated and peristaltic contractions in-vitro. The present experiments examined the contractile response to a series of benzamides in the guinea-pig non-stimulated ileum. Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine (% acetylcholine response = 12 +/- 2, 19 +/- 3, 26 +/- 2, 51 +/- 3, n = 13, 8, 17, and 21, with EC50 values of 0.85, 1.8, 5.7, and 14.2 microM for cisapride, zacopride, metoclopramide, and ML-1035 (4-amino-5-chloro-2-((2-methylsulphinyl)-ethoxy)-N- (2-(diethylamino)-ethyl)-benzamide hydrochloride), respectively). ML-1035 contractions were completely blocked by atropine and tetrodotoxin, while ganglionic blockade with hexamethonium was ineffective. Metoclopramide has been reported to sensitize postjunctional muscarinic receptors, however, ML-1035 did not enhance acetylcholine-induced contractions. Tropisetron (ICS 205-930, 1 microM), caused a parallel rightward shift in the concentration-response curve for both ML-1035 and zacopride (EC50 = 14.2 +/- 1.3 and 1.8 +/- 0.8 microM in the absence, and 26 +/- 2.7 and 6.9 +/- 2.3 microM in the presence of tropisetron for ML-1035 and zacopride, respectively) with apparent pKB values of 5.9 and 6.0 for the respective compounds. 5-Hydroxytryptaminergic receptor desensitization by 2-methyl-5-hydroxytryptamine (5-HT3) and 5-methoxytryptamine (5-HT4), attenuated the response to ML-1035.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Marion Merrell Dow Research Institute, Department of CNS Research, Cincinnati, OH 45215-6300.
authors.forename: M D
authors.initials: MD
authors.lastname: Linnik
authors.forename: B T
authors.initials: BT
authors.lastname: Butler
authors.forename: S H
authors.initials: SH
authors.lastname: Elsea
authors.forename: N K
authors.initials: NK
authors.lastname: Ahmed
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008787:Metoclopramide / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D001549:Benzamides; D013779:Tetrodotoxin; C071737:ML 1035; D008787:Metoclopramide; D000109:Acetylcholine