Synthesis and adrenergic activity of ring-fluorinated phenylephrines

2-Fluoro-, 4-fluoro-, and 6-fluorophenylephrine (6-FPE) were synthesized from the corresponding fluorinated 3-hydroxybenzaldehydes. New routes to 2-fluoro- and 6-fluoro-3-hydroxybenzaldehydes were developed based on regioselective lithiation of 2- and 4-[(dimethyl-tert-butylsilyl)oxy]fluorobenzene ortho to fluorine. As with norepinephrine and isoproterenol analogues, the adrenergic properties of phenylephrine were markedly altered by ring fluorination. The order of potency of the fluoro analogues as alpha 1-adrenergic agonists in the stimulation of contraction of aortic strips and of phosphatidylinositol turnover and potentiation of cyclic AMP accumulation in guinea pig synaptoneurosomes was 6-FPE greater than PE greater than 4-FPE greater than 2-FPE. The same pattern was observed for the displacement of radioligands specific for alpha 1- and alpha 2-adrenergic receptors on brain membranes. The order of potency for the displacement of [3H]dihydroalprenolol, a beta-specific adrenergic ligand from brain membranes, was 2-FPE greater than 4-FPE = PE much greater than 6-FPE. 6-FPE was much more selective for alpha-adrenergic receptors compared to beta-receptors than was phenylephrine. A rationale for the observed fluorine-induced alterations in potency and selectivity of the FPEs for alpha- and beta-adrenergic systems is presented based on fluorine-induced conformations due to electrostatic repulsion of fluorine and the benzyl hydroxyl group.