Research activities are concerned with chemical aspects of drug metabolism and drug action from mechanistic and stereochemical viewpoints. Many drugs are used as racemic mixtures in which the optical isomers (enantiomers) have different pharmacological or toxicological properties, as well as different rates or pathways of metabolism. We are particularly interested in exploring pathways of the metabolism of cardiovascular drugs, agents widely used for the treatment of hypertension and other diseases. Among these are the b-adrenergic blocking agents and calcium channel antagonists. We have prepared enantiomers labeled specifically with deuterium or 13C, and we are studying the metabolism of the compounds as pseudoracemates (equimolar mixtures of the enantiomers in which only one of the enantiomers is labeled). Thus, we are able to determine the individual enantiomers by GC-mass spectrometry on the basis of differential molecular weights. A number of putative metabolites are synthesized to confirm their identity. Expected intermediates in metabolic processes and diastereomeric metabolites of known stereochemistry are synthesized, identified and quantitated. In this way, we can examine the metabolic pathways for their formation to obtain an understanding of how the drugs are metabolized. Much of the work is done in tissue homogenates from humans and rats, purified enzymes and occasionally in vivo.

In addition, we are exploring configurational aspects of drugs as they are related to interaction at substances of opioid receptors. Our work is centered on preparation of selective ligands for k-, m- and d- opioid receptors with electrophilic groups that may interact with nucleophilic centers at or near reactive groups as part of the various receptors. The compounds have a potential to aid in characterization of these drug receptors and may provide long-lived pharmacological responses.

Recent Publications:

• M. Kim, L. K. Roskos, D. D. Shen, A. C. Eddy and W. L. Nelson, "Inhibition of the Enantioselective Oxidative Metabolism of Metoprolol by Verapamil in Human Liver Microsomes," Drug Metab. Dispos., 21, 309-317 (1993).
• T. A. Bowdle and W. L. Nelson, "Clinical Pharmacology of Partial Agonist, Mixed Agonist and Antagonist Opioids," in the Pharmacological Basis of Anesthesiology, 1994, T. A. Bowdle, A. Horita and E. D. Kharasch, ed., Chapter 4, pp 121-148, Churchill-Livingston, New York.
• P. H. Marathe, D. D. Shen and W. L. Nelson, "Metabolic Kinetics of Pseudoracemic Propranolol in Human Liver Microsomes. Enantioselectivity and Quinidine Inhibition," Drug Metab. Dispos., 22, 237-247 (1994).
• S. A. Weerawarna, R. D. Davis and W. L. Nelson, "Isothiocyanate Substituted k-Selective Opioid Receptor Ligands Derived from N-Methyl-N[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]phenylacetamide," J. Med. Chem., 37, 2856-2864 (1994).
• T. D. Nelson, R. D. Davis and W. L. Nelson, "Synthesis and Opioid Receptor Affinity of a Series of Aralkyl Ethers of 6a-and 6b-Naltrexol," J. Med. Chem., 37, 4270-4277 (1994).
• R. D. Davis and W. L. Nelson, "Isothicyanate Substituted Benzyl Ether Opioid Receptor Ligands Derived from 6b-Naltrexol," J. Med. Chem., 38, 570-519 (1995).
• D. S. Mautz, W. L. Nelson and D. D. Shen, "Regioselective and Stereoselective Oxidation of Metoyrolol and Bufuralol Catalyzed by Microsomes Containing cDNA-Expressed Human P4502D6," Drug Metab. Dispos., 23, 512-517 (1995).
• D. S. Mautz, D. D. Shen and W. L. Nelson, "Regioselectivity and Enantioselectivity of Metoprolol Oxidation by Two Variants of cDNA-expressed P4502D6," Pharm. Res., 12, 2053-2056 (1995).
• R. B. Palmer, A. L. Upthagrove and W. L. Nelson, "(E)- and (Z)-7-arylidenenaltrexones: Synthesis and Opioid Receptor Radioligand Displacement Assays," J. Med. Chem., 40, 749-753 (1997).
• A. L. Upthagrove, M. Hackett and W. L. Nelson, "Fragmentation Pathways of Selectively Labeled Uropranolol Using Electrospray Ionization on an Ion Trap Mass Spectrometer and Comparison with Ions Formed by Electron Impact," Rapid Commun. Mass Spectrom., 13, 534-541 (1999).
• A. L. Upthagrove, M. Hackett and W. L. Nelson, "Mass Spectral Fragmentation Pathways of Propranolol Related Beta-Fluorinated Amines Studied by Electrospray and Electron Impact Ionization," Rapid Commun. Mass Spectrom., 13, 1671-1679 (1999).
• A. L. Upthagrove and W. L. Nelson, "Carbinolamines, Imines, and Oxazolidines From Fluorinated Propranolol Analogs (19)f NMR and Mass Spectral Characterization and Evidence for Formation as Intermediates in Cytochrome p450-catalyzed n-dealkylation," Drug Metab. Dispos., 29, 1114-1122 (2001).
• W. L. Nelson, "Chapter 33. Antihistiamines and Related Anti-allergic and Anti-ulcer Agents," in Principles of Medicinal Chemistry, 5th Edition, D. A. Williams and T. L. Lemke, editors, in press.
• A. L. Upthagrove and W. L. Nelson, "Importance of Amine pKa and Distribution Coefficient in the Metabolism of Fluorinated Propranolol Analogs. Preparation, Identification of Metabolite Regioisomers and Metabolism by CYP2D6," Drug Metab. Dispos., in press.
• A. L. Upthagrove and W. L. Nelson, "Importance of Amine pKa and Distribution Coefficient in the Metabolism of Fluorinated Propranolol Analogs. Metabolism by CYP1A2," Drug Metab. Dispos., in press.

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This page last updated: June 17, 2002