Fluorinated Catecholamines? ? The important and diverse biological functions of adrenergic agonists have made the search for compounds that selectively stimulate or inhibit the activity of the different types of adrenergic receptors an important area of medicinal chemistry. In the 1980s we synthesized 2-,5-, and 6-flouronorepinehprine (FNE) and 2-,5-, and 5-fluoroepineprhine (FEPI) and found that fluorine in the 2-position inhibited binding to alpha-adrenergic receptors and fluorine in the 6-position of inhibited binding to beta-adrenergic receptors. We previously carried out a combination of molecular modeling (docking experiments) and site specific mutagenesis to attempt to identify which amino acid residues on these receptors are responsible for fluorine-induced adrenergic selectivities. Work continues on development of models to explain these fluorine-induced selectivitities.? ? Fluorinated Indoles? ? We had previously prepared 4-fluoro, 5-fluoro-, 6-fluoro-, 7-fluoro, 4,6-difluoro, and 4,7-difluoroserotonin and melatonins to study the effects of fluorine substitution on the biological properties of these important bioindoles. ? ? The affinities of the ring-fluorinated serotonins have been evaluated at 5HT1A, 5HT2A, 5HT2B, and 5HT5A receptors. Although there are individual differences in binding, the trends and orders of magnitude for the fluorinated compounds were comparable to serotonin. Thus, ring fluorination appears not to have dramatic effect such as seen with the adrenergic agonists, norepinephrine and epinephrine.? ? A functional assay was carried out with the fluorinated analogues of melatonin. There were only small effects of ring fluorination observed on the action of melatonin on xenopus melanophore pigment aggregation. 7-Fluoro- and 6,7-difluoromelatonin were approximately one order of magnitude less potent than melatonin and the other fluorinated analogues. Binding to the hMT1 and hMT2 receptors likewise showed only small effects of fluorination. The 6,7-difluoroanalogue had slightly reduce affinity. ? ? A capsaicin fluorine scan.? ? Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the main pungent component in hot chili peppers. It binds to the vanilloid receptor subtype 1 (VR1), an ion type channel responsive to heat, physical abrasion or acidic pH, explaining the hot or burning sensation perceived after consumption. Because of increased interest in the utilization of this receptor system for applications of pain alleviation, we have undertaken an investigation of the effects of fluorine substitution on the aromatic moiety of capsaicin on the receptor affinity (a fluorine scan). ? ? With successful synthesis of fluorinated capsaicin analogue substituted at 5 and 6 position, binding assays were performed with the natural capsaicin and fluorinated analogues on the rat vanilloid receptor subtype 1 (rVR1), expressed in HEK293 cells. These studies revealed no significant changes in affinity towards the vanilloid receptor between the natural capsaicin and the 5- or 6-fluorocapsaicin.? ? We encountered numerous difficulties in synthesizing the 2-fluorocapsaicin. We recently improved the synthesis of the required 2-fluorovanillin using our recently developed photochemical Schiemann procedure in ionic liquid. We are now completing the synthesis of 2-fluorocapsacin and its affinity to rVR1 will then be measured.
| Pooput, Chaya; Rosemond, Erica; Karpiak, Joel et al. (2009) Structural basis of the selectivity of the beta(2)-adrenergic receptor for fluorinated catecholamines. Bioorg Med Chem 17:7987-92 |
| Hruschka, Svenja; Rosen, Thomas C; Yoshida, Shinichi et al. (2008) Fluorinated phenylcyclopropylamines. Part 5: Effects of electron-withdrawing or -donating aryl substituents on the inhibition of monoamine oxidases A and B by 2-aryl-2-fluoro-cyclopropylamines. Bioorg Med Chem 16:7148-66 |
| Hruschka, Svenja; Yoshida, Shinichi; Kirk, Kenneth L et al. (2008) Fluorinated phenylcyclopropylamines. Part 6: Effects of electron withdrawing or donating aryl substituents on the inhibition of tyramine oxidase from Arthrobacter sp. by diastereomeric 2-aryl-2-fluoro-cyclopropylamines. J Fluor Chem 129:875-880 |
