title: Synthesis and pharmacological properties of azido derivatives of 1,5-benzothiazepine Ca antagonist.
abstract: Since azido derivatives of 1,5-benzothiazepine Ca antagonist available for photoaffinity labeling are required for further studies of voltage-sensitive Ca channels, we synthesized 3-(p-azidobenzoyloxydeacetyl)- and 3-(4-azidobutyryloxydeacetyl)-diltiazem, and studied their pharmacological properties. Both azido compounds showed similar relaxing actions to diltiazem in K(+)-depolarized dog arteries. They also showed a similar increasing action to diltiazem, but less potent, on the coronary and vertebral blood flow in the anesthetized dog. Moreover, their negative inotropic effects in the guinea pig papillary muscle were similar to or slightly more potent than that of diltiazem under physiological conditions, but were less potent when studied in K+ depolarizing solution. A radioligand binding study in rat skeletal muscle microsomes revealed that the azido derivatives had similar properties to diltiazem, but the nonspecific binding of 3-(p-azidobenzoyloxydeacetyl)-diltiazem was too high to allow estimation of its KD and Bmax values. In conclusion, we synthesized azido derivatives of diltiazem which were considered to share a common binding site on the voltage-dependent Ca channel with diltiazem in skeletal muscle microsomes and in vascular smooth muscle.
authors.affiliation: Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Narita
authors.forename: M
authors.initials: M
authors.lastname: Gaino
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Kurosawa
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Nagao
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009568:Nitrendipine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; C064175:3-(4-azidobenzoyloxy)diltiazem; D009568:Nitrendipine; D004110:Diltiazem