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 analogs. 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 alpha-adrenergic agonist and 2-fluoronorepinephrine 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. The results of testing of new analogs synthesized to probe these mechanisms have not clearly differentiated between these two basic mechanisms. Binding of fluorinated analogs to cloned wild-type and mutant adrenergic receptors is now being studied to try to identify specific sites on the receptor protein responsible for fluorine-induced adrenergic selectivities. Fluorinated analogs are useful mechanistic probes and biological tracers. [18F]-labeled 6-fluorodopamine, the biological precursor to 6-fluoronorepinephrine, has been found to be an excellent scanning agent for peripheral noradrenergic innervation. We have developed stereoselective syntheses of threo-2- and 6- fluorodihydroxyphenylserine (fluoro-DOPS). These will be studied as prodrugs for the elaboration of 2-and 6-fluoronorepinephrine in the central nervous system. Diasteroselective and enantioselective approaches to [18F]-labelled-threo-6-fluoro-DOPS as a PET-scanning agent for central adrenergic innervation have been developed. A new synthesis of fluorinated and polyfluorinated veratraldehydes, based on direct electrophilic fluorination, has been realized.