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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034052-02
Application #
3346614
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1985-04-01
Project End
1988-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Pharmacy
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Mutlib, A E; Nelson, W L (1990) Pathways of gallopamil metabolism. Regiochemistry and enantioselectivity of the O-demethylation processes. Drug Metab Dispos 18:309-14
Mutlib, A E; Nelson, W L (1990) Synthesis and identification of the N-glucuronides of norgallopamil and norverapamil, unusual metabolites of gallopamil and verapamil. J Pharmacol Exp Ther 252:593-9
Theodore, L J; Nelson, W L; Dave, B et al. (1990) Studies on Ca2+ channel antagonists. A 2-diazo-3,3,3-trifluoropropionamide derivative related to verapamil as a potential photoaffinity probe. J Med Chem 33:873-7
Mutlib, A E; Nelson, W L (1990) Pathways of gallopamil metabolism. Regiochemistry and enantioselectivity of the N-dealkylation processes. Drug Metab Dispos 18:331-7
Nelson, W L; Olsen, L D (1988) Regiochemistry and enantioselectivity in the oxidative N-dealkylation of verapamil. Drug Metab Dispos 16:834-41
Nelson, W L; Olsen, L D; Beitner, D B et al. (1988) Regiochemistry and substrate stereoselectivity of O-demethylation of verapamil in the presence of the microsomal fraction from rat and human liver. Drug Metab Dispos 16:184-8
Grossi, E A; Krieger, K H; Cunningham Jr, J N et al. (1986) Time course of effective interventional left heart assist for limitation of evolving myocardial infarction. J Thorac Cardiovasc Surg 91:624-9
Theodore, L J; Nelson, W L; Zobrist, R H et al. (1986) Studies on Ca2+ channel antagonists. 5-[(3,4-Dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2- isopropylpentyl isothiocyanate, a chemoaffinity ligand derived from verapamil. J Med Chem 29:1789-92