Burnett D M, Gal J, Zahniser N R, Nies A S
Department of Medicine, University of Colorado Health Sciences Center, Denver.
J Cardiovasc Pharmacol. 1988;12(5):615-9. doi: 10.1097/00005344-198811000-00017.
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.
为了确定新型抗心律失常药物普罗帕酮是否与β-肾上腺素能受体发生立体选择性相互作用，使用体外结合试验测定了（-）和（+）异构体的效价。（-）-普罗帕酮是更有效的异构体，在大鼠大脑皮质和小脑膜中以简单的方式与125I-吲哚洛尔竞争，Ki值分别为32±1.7和77±5.8 nM。相比之下，同一组织中（+）-普罗帕酮的竞争曲线更为复杂，显示出两个结合位点，其亲和力比（-）-普罗帕酮低10至75倍。此外，通过高效液相色谱（HPLC）分析发现（+）-普罗帕酮被3%更有效的（-）-异构体污染；这种污染占了（+）-普罗帕酮大部分的表观活性。这些数据表明，普罗帕酮与β1和β2受体的相互作用对（-）异构体具有明显的立体选择性。（-）异构体对β-肾上腺素能受体的阻断可能是普罗帕酮治疗中报道的一些不良临床效应的原因。
