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 (6-FNE) is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine (2- FNE) is a selective beta-adrenergic agonist. Mechanisms considered to explain these results include: 1) a direct effect of the C-F bond on agonist-receptor interaction or 2) an indirect effect of the C-F bond on the conformation of the ethanolamine side-chain. To have available alternative biosynthetic precursors of 2-FNE and 6-FNE, we have developed stereoselective syntheses of threo-2- and 6- fluorodihydroxyphenylserine (threo-FDOPS). Initial biological testing suggests that these analogues may be poor substrates for decarboxylase enzymes. We have prepared the complete series of fluorinated and polyfluorinated dopamines, norepinephrines, and DOPAs from the corresponding veratraldehydes, recently prepared by us using electrophilic fluorination of aromatic substrates. Examination of the interactions of the mono-, di-, and trifluoroanalogues of dopamine with D-1, D-2, D-3 and D-4 dopamine receptors, and alpha-1 and alpha-2 adrenergic receptors has been carried out. Fluorinated analogues of irreversible dopamine beta-hydroxlyase (DBH) inhibitors have been prepared as a first step toward the development of DBH-targeted irreversible ligands for PET imaging of central adrenergic innervation. Aminocyclopropane carboxylic acid (ACCA) has been shown by others to provide protection from damage due to stroke to central neurons. Monofluoro- and gem-Difluoroaminocyclopropane carboxylic acids have been prepared. Initial biological evaluation indicates that the monofluoro analogue is equipotent with ACCA. Fluorinated ACCAs are also alpha-flouromethylene amino acids, a class of derivative known to be effective inhibitors of PLP-dependent enzymes.