title: Synthesis, characterization, and Ca2+ antagonistic activity of diltiazem metabolites.
abstract: Diltiazem is a calcium antagonist widely used in the treatment of angina and hypertension. The contributions of metabolites of diltiazem to the vasorelaxant effects of diltiazem were investigated. The synthesis and spectroscopic characterization of eight major cis-diltiazem metabolites are described. Three of the compounds--N, O-didemethylated metabolite (21), O-demethylated metabolite (22), and diltiazem N-oxide (27)--have been recently reported and have not previously been synthesized. The identities of all eight synthetic metabolites have been verified with samples obtained from human urine using combined LC-MS/MS. The Ca2+ antagonistic activities of diltiazem and its metabolites (except 27) were studied on hamster aorta preparations depolarized with KCl. The order of potencies (IC50 +/- SE, microM) is as follows: diltiazem (0.98 +/- 0.47) greater than 17 (2.46 +/- 0.38) greater than or equal to 23 (3.27 +/- 1.02) greater than 26 (20.2 +/- 10.5) greater than 22 (40.4 +/- 15.4) greater than or equal to 25 (45.5 +/- 18.1) greater than 21 (112.2 +/- 33.2) greater than or equal to 24 (126.7 +/- 24.2). Structure-activity relationships are also discussed.
authors.affiliation: College of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.forename: P S
authors.initials: PS
authors.lastname: Farmer
authors.forename: M
authors.initials: M
authors.lastname: Xie
authors.forename: M A
authors.initials: MA
authors.lastname: Quilliam
authors.forename: S
authors.initials: S
authors.lastname: Pleasance
authors.forename: S E
authors.initials: SE
authors.lastname: Howlett
authors.forename: P K
authors.initials: PK
authors.lastname: Yeung
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004110:Diltiazem / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D013058:Mass Spectrometry; D008968:Molecular Conformation; D015394:Molecular Structure; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D004110:Diltiazem