ABSTRACT
In order to test a hypothesis that the seven-membered ring of the benzothiazepinone (diltiazem) and benzazepinone calcium channel blockers serves primarily to orient two critical pharmacophores in space, a series of novel, conformationally constrained bicyclo[2.2.2]octyl amines 3 which severely restrict the relative orientations available to the amine and methoxyphenyl groups was prepared. All compounds which positioned the pharmacophores on the same face of the molecule demonstrated vasorelaxant activity and affinity for the diltiazem receptor equal to or greater than racemic diltiazem 1 or the corresponding benzazepione 2. In addition, compound 3d was equipotent to (+)-diltiazem in its ability to reduce ischemic/reperfusion injury in an in vitro model of myocardial ischemia. However, 3d is significantly less cardiodepressive at an equivalent antiischemic dose. Therefore, the original receptor binding hypothesis led to the design and synthesis of novel calcium channel blockers with unique biological properties.
Subject(s)
Benzazepines/chemistry , Calcium Channel Blockers/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacology , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacology , Diltiazem/analogs & derivatives , Diltiazem/chemistry , Diltiazem/pharmacology , Drug Design , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Molecular Conformation , Molecular Structure , Myocardial Ischemia/drug therapy , Myocardial Reperfusion Injury/prevention & control , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
In order to determine whether CCl4, CBrCl3, CBr4 or CHCl3 undergo oxidative metabolism to electrophilic halogens by liver microsomes, they were incubated with liver microsomes from phenobarbital pretreated rats in the presence of NADPH and 2,6-dimethylphenol. The analysis of the reaction mixtures by capillary gas chromatography mass spectrometry revealed that 4-chloro-2,6-dimethylphenol was a metabolite of CCl4 and CBrCl3 whereas 4-bromo-2,6-dimethylphenol was a metabolite of CBr4. The formation of the metabolites was significantly decreased when the reactions were conducted with heat denatured microsomes, in the absence of NADPH or under an atmosphere of N2. These results indicate that the chlorines of CBrCl3 and CCl4 and the bromines of CBr4 are oxidatively metabolized by rat liver microsomes to electrophilic and potentially toxic metabolites.
