Propafenone interacts stereoselectively with beta 1- and beta 2-adrenergic receptors.
In order to determine whether the new antiarrhythmic agent propafenone interacts stereoselectively with beta-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 Ki 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 beta 1- and beta 2-receptors are markedly stereoselective for the (-) isomer. It is possible that beta-adrenergic receptor blockade by the (-) isomer may be responsible for some of the adverse clinical effects that have been reported with propafenone therapy.
Burnett
D M
DM
Department of Medicine, University of Colorado Health Sciences Center, Denver.
Gal
J
J
Zahniser
N R
NR
Nies
A S
AS
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D010869:Pindolol; D011405:Propafenone / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013237:Stereoisomerism
D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D011405:Propafenone; D010869:Pindolol