HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

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Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with fluorine substituted at various ring-positions. By virtue of its very small size and high electronegativity, fluorine is a very favorable replacement for hydrogen in these analogues. The biological properties and usefulness of these ring-fluorinated biogenic amines have proved to be extremely rewarding and continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-fluoronorepinephrine is a selective beta-adrenergic agonist and 2- fluoronorepinephrine is a selective beta-adrenergic agonist. Because our previous syntheses of FNE's produced racemic material, we have investigated routes to the pure R-enantiomers. We have examined asymmetric aminohydroxylation reactions, enantioselective Darzens reactions, and the use of chiral Lewis acids to catalyze aldol reactions. Although non-racemic products have been obtained, additional research is need to realize acceptable yields. In order to have available alternate biological precursors for 2-FNE and 6-FNE, we previously synthesized threo-2- and 6-fluorodihydroxy-phenylserine (fluoro-DOPS) in the racemic form, but found these analogues to be poor substrates for aromatic amino acid decarboxylase. This may be due to inhibition of decarboxylation of the 2S-isomer by the 2R-isomer Using similar strategies as applied to the synthesis of chiral FNE's, we are examining routes to homochiral (2S,3R)-fluoro-DOPS. Fluorinated arylacetylenic amines were prepared and examined as inhibitors of dopamine beta-hydroxylase.