Propafenone Interacts Stereoselectively with β1 and β2-Adrenergic Receptors

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Abstract
In order to determine whether the new antiarrhythmic agent propafenone interacts stereoselectively with β-adrenergic receptors, the potencies of both the (-) and (+) isomers were determined using in vitro binding assays. (-)-Propafenone was the more potent isomer and competed with 125I-pindolol in a simple manner in both rat cerebral cortical and cerebellar membranes with K1 values of 32 ± 1.7 and 77 ± 5.8 nM, respectively. In contrast, competition curves for (+)-propafenone in the same tissues were more complex and revealed two binding sites with affinities 10− to 75-fold less potent than those for (-)-propafenone. Moreover, the (+)-propafenone was found by high performance liquid chromatography (HPLC) analysis to be contaminated with 3% of the more potent (-)-isomer; this contamination accounted for most of the apparent activity of the (+)-propafenone. These data suggest that interactions of propafenone with both β1- and β2-receptors are markedly stereoselective for the (-) isomer. It is possible that β-adrenergic receptor blockade by the (-) isomer may be responsible for some of the adverse clinical effects that have been reported with propafenone therapy.

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