title: Studies on calcium antagonistic and alpha 1-adrenergic receptor blocking activities of monatepil maleate, its metabolites and their enantiomers.
abstract: The calcium antagonistic and alpha 1-adrenergic receptor blocking activities of monatepil maleate (CAS 103377-41-9, (+/-)-N-(6,11-dihydrodibenzo [b, e] thiepin-11-yl) -4-(4-fluorophenyl)-1-piperazinebutanamide monomaleate, AJ-2615), a novel calcium antagonist, its metabolites and their enantiomers were studied in vitro. Monatepil maleate inhibited calcium-induced contractions of rat thoracic aorta (pA2 = 8.71) and l-phenylephrine-induced contractions of rabbit superior mesenteric artery (IC50 = 56.6 nmol/l). The calcium antagonistic activities of the metabolites of monatepil maleate (AJ-2615-sulfoxide A, AJ-2615-sulfoxide B and AJ-2615-sulfone) were 1/10 of that of monatepil maleate. However, their alpha 1-adrenergic receptor blocking activities were similar to or slightly more potent than that of monatepil maleate. The potencies of the calcium antagonistic activities of monatepil maleate and its enantiomers [(S)-AJ-2615 and (R)-AJ-2615] were in the order of (S)-AJ-2615 > monatepil maleate > (R)-AJ-2615 whereas no difference was observed among them in alpha 1-adrenergic receptor blocking activity. In calcium antagonistic and alpha 1-adrenergic receptor blocking activities, there was no difference between the enantiomers of monatepil maleate metabolites. In conclusion, there was a difference with several times in calcium antagonistic activity between the two enantiomers of monatepil maleate but not in their alpha 1-adrenergic receptor blocking activity.
authors.affiliation: Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Honda
authors.forename: Y
authors.initials: Y
authors.lastname: Masuda
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: F
authors.initials: F
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
authors.forename: K
authors.initials: K
authors.lastname: Hosoki
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D003988:Dibenzothiepins / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D003988:Dibenzothiepins; D010879:Piperazines; D010656:Phenylephrine; C067818:monatepil