The aims of this proposal are related to chemical and stereochemical aspects of metabolic processes that occur in two important slow calcium channel antagonists verapamil and D-600. Work is proposed which will delineate pathways of metabolite formation and provide a source of the enantiomers of these compounds to facilitate pharmacogical studies and studies on stereoselectivity of the metabolic processes. Structures of metabolites of verapamil and of D-600 will be determined by GC-MS comparison with standards of known structure. Stereoselectivity of metabolic processes will be studied using pseudoracemic mixtures of the enantiomers of verapamil and D-600. A suitable deuterium labeling procedure that is readily applicable to the individual enantiomers without racemization has been found. Deuterium labeling and use of pseudoracemic substrates will facilitate determination of metabolites arising from dealkylation of either the longer or short side chain. Mechanistic aspects of the N-dealkylation process will be examined on verapamil by determining carbonyl compounds and iminium ions which arise by metabolic N-dealkylation. Specifically deuterated verapamil will also be used to determine whether an equilibrium exists between iminium ions. Methods for the analysis of individual enantiomers of verapamil and D-600 will be explored to determine whether it is possible to determine the individual enatiomers from samples containing racemic (non-pseudoracemic) compound. Diastereomeric derivatization will be performed on reduction products of verapamil and D-600.
