Effect of Fluorine Substitution on the Adrenergic Properties of 3-(tert-Butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol

The 2- and 6-fluoro derivatives of the potent β-adrenergic agonist 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol were prepared and their adrenergic properties examined. The order of potency was as follows: β-adrenergic activity (simulation of cyclic AMP formation in C6 glioma cells), 2-F = parent ≫ 6-F; β₁-activity (rate of contraction, guinea pig atria), parent > 2-F ≫ 6-F; β₂-activity (relaxation of guinea pig tracheal strip), 2-F > parent ≫ 6-F. The affinity of the 2-fluoro analogue for β₁-adrenergic receptors (inhibition of the specific binding of [³H]dihydroalprenolol, rat cerebral cortical membranes) was 2 times greater, while the 6-fluoro analogue was 1450 times less than the parent. These results suggest that the aromatic rings of phenoxypropanolamine adrenergic agonists and phenylethanolamine adrenergic agonists bind in similar fashion to the adrenergic receptor, and that if interactions between fluorine and the side-chain hydroxyl group are critical in defining β-adrenergic selectivity, the interactions are similar in both phenoxypropanolamines and phenylethanolamines.