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 flourine substituted at various ring-positions. By virtue of its very small size and high electronegativity, flourine 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-flouronorepinephrine 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 analogues synthesized to probe these mechanisms have not clearly differentiated between these two basic mechanisms. Binding of fluorinated analogues to cloned wild-type and mutant adrenergic receptors has been carried out in an attempt to identify specific sites on the receptor protein responsible for fluorine-induced adrenergic selectivities. We have developed stereoselective syntheses of threo-2-and 6- fluorodihydroxyphenylserine (fluoro-DOPS). A new synthesis of fluorinated and polyfluorinated veratraldehydes, based on direct electrophilic fluorination, has been realized, and we have prepared all mono- and difluorinated analogues of veratraldehyde as well as trifluorovertraldehyde. These are being used to prepare the corresponding biogenic amines and their amino acid precursors. Examination of the interactions of the mono-, di-, and trifluoroanalogues of dopamine with D-1, D-2, and D-3 dopamine receptors has been carried out. Aminocyclopropane carboxylic acid (ACCA) has been shown by others to provide protection from damage due to stroke of central neurons.