Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Ring-fluorinated analogs have proved to be powerful tools for the study of the mechanisms of transport, storage, release, metabolism and modes of action of these amines since they simulate the geometries of the natural compounds so well. By virtue of its very small size and high electronegativity, fluorine should be a very favorable replacement for hydrogen in these analogs. Some years ago, we developed novel methods for the introduction of fluorine into organic molecules and have applied these methods to the syntheses of a wide variety of biogenic amines with fluorine at various ring positions. The biological properties and usefulness of these ring-fluorinated biogenic amines has proved to be extremely rewarding and continue to find application in a multitude of studies. Perhaps the most significant finding, to date, is that 6-fluoronorepinephrine is a pure alpha-adrenergic agonist, while the 2-fluoro epinephrine is a pure beta-adrenergic agonist. Various explanations for the role of fluorine in creating such specificity have been considered and discarded. We now propose that a critical dipole-dipole repulsion between the benzyllic hydroxyl group and fluorine in the 2- or 6-position confers side chain conformational preference favorable for interaction with the beta- and alpha-adrenergic receptor, respectively. The discovery of increased potency in a fluorinated alpha-adrenergic agonist has both practical and theoretical importance. Chemo-enzymatic methods have been used to prepare radiolabeled fluorinated analogs as well as new analogs as potential prodrugs for melanoma chemotherapy.
