The chemistry, biochemistry, physiology, and pharmacology of biogenic amines, their amino acid precursors and metabolic products, and various synthetic derivatives have been investigated. The areas of interest include catechol-O-methyltransferase (COMT) and the effects of fluorine substitution on the properties of biogenic amines and amino acids. These include 1) development of improved methodology for the purification of COMT, utilizing high pressure liquid chromatography, 2) enzymatic hydrolysis, isolation, and determination of the primary sequence of peptides derived from COMT, 3) preparation of oligonucleotides from COMT-specific peptide sequences and the identification clones from rat liver. 4) immunohistochemical localization of COMT in normal, and malignant tissues of rodent and man at the light and electron microscopic level. The tissues include: a) the gastrointestinal track of rat and man, b) the ovary, uterus and oviduct in virginal and pregnant golden hamster, c) hormonally sensitive and insensitive human breast tumors, d) neuroepithelial bodies associated with adrenergic innervation of lung, e) macrophages from rat ovary, f) fibroblasts present in dental pulp, and 8) normal human skin, premelanotic nevi, and malignant melanoma. 5) the substrate specificity and reaction mechanism of COMT including a) O-methylation of (S)- and (R)-dideoxynorlaudanosoline-l-carboxylic acids, and a series of related non-catecholic quinone methines as possible precursors of endogenous mammalian opiates, b) the effects of subsitution of fluorine at the 2,5, and 6 carbons on the aromatic ring of epinephrine on the affinity and reaction rates with COMT, c) the effects of disubstitution of fluorine at the 2,5- and 2,6-carbons of norepinephrine on the affinity and reaction rates with COMT, d) the effects of fluorine substitution on the aromatic ring of dihydrophenylserines on the interaction parameters of COMT, 6) the alpha- and beta-adrenergic properties of fluorine substituted catecholamines and related compounds, 7) the mechanism of toxicity of 6-fluoro-2,6-difluorophenylalanine and 6-fluoro- and 2,6- difluorotyrosine in cultured pheochromocytoma and melanoma cell lines.
