title: New calcium antagonists: synthesis, X-ray analysis, and smooth muscle relaxing effect of 3-[O-(benzyl-substituted)-oximino-ethers]-hexahydroazepin-2,3- diones.
abstract: A series of new Z and E 3-[O-(benzyl-substituted)-oximino-ether]-hexahydroazepin-2,3 -diones was prepared from the corresponding hexahydroazepin-2,3-diones and examined as smooth muscle relaxants. E and Z structures were assigned by NMR analysis and confirmed for 16 (E and Z) by an X-ray diffraction using synchrotron radiations. The nitrobenzyl derivative 16 was the most potent in vitro as relaxant of rat trachea precontracted with acetylcholine. The E isomer 16b was more potent than the Z isomer 16a. E isomer 16b is more potent than aminophylline to relax both rat trachea and human bronchus. This derivative acts mainly by inhibiting cellular influx of extracellular calcium since it inhibits potently and dose-dependently the contractions of rat trachea to high concentrations of KCI and to CaCl2 in a depolarizing medium. It appears to act weakly by inducing cGMP and cAMP synthesis. Moreover, its relaxing activity is not related to an inhibition of phosphodiesterases, to opening of potassium channels or to induction of prostaglandin synthesis. Therefore, 16b appears to work mainly as a potent calcium antagonist.
authors.affiliation: Groupe de Pharmacochimie Moléculaire, EP 811 CNRS, UFR de Pharmacie, Université Joseph Fourier, Meylan, France.
authors.forename: H
authors.initials: H
authors.lastname: El From
authors.forename: M H
authors.initials: MH
authors.lastname: Péra
authors.forename: G
authors.initials: G
authors.lastname: Leclerc
authors.forename: D
authors.initials: D
authors.lastname: Tranqui
authors.forename: E
authors.initials: E
authors.lastname: Corompt
authors.forename: G
authors.initials: G
authors.lastname: Bessard
authors.forename: P
authors.initials: P
authors.lastname: Devillier
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D001381:Azepines; D002118:Calcium