The effects of the stereoisomers of propafenone and diprafenone in guinea‐pig heart

Abstract

1 Optically pure enantiomers of propafenone and diprafenone were prepared from their racemic mixtures and tested for their ability to block fi-adrenoceptors and to prolong functional refractory period in the guinea-pig heart. fi-Adrenoceptor affinity of the enantiomers was determined by the radioligand binding technique and in functional experiments.2 Propafenone and diprafenone inhibited specific binding of the fi-adrenoceptor antagonist (-)-[3H]-CGP-12177 to guinea-pig myocardial membranes. f,-Adrenoceptor affinities of diprafenone enantiomers exceeded those of corresponding propafenone enantiomers by one order of magnitude. Displacement of (-)-[3H]-CGP-12177 by both antiarrhythmics was highly stereoselective, in that the (S)-enantiomers were 40-60 fold, i.e. 1.6-1.8 log units more potent than the (R)-enantiomers. 3 Propafenone and diprafenone antagonized the positive inotropic action of isoprenaline in isolated atria. fi-Adrenoceptor antagonist potencies of diprafenone enantiomers were about one order of magnitude higher than those of corresponding propafenone enantiomers. For both drugs the (S)-enantiomer was found to be considerably more potent (14-40 fold) than the (R)-enantiomer. 4 Propafenone and diprafenone prolonged functional refractory period of isolated auricles with equal potency and no difference in the antiarrhythmic activity of purified enantiomers was found. 5 It is concluded that the enantiomers of propafenone and diprafenone exert comparable antiarrhythmic activity, whereas only (S)-enantiomers block cardiac fi-adrenoceptors with high affinity, which explains the fi-adrenoceptor antagonist effects of the racemic drugs.

Electrophysiological properties of the propafenone-analogue GE 68 (1-[3-(phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol) in isolated preparations and ventricular myocytes of guinea-pig hearts

“…Racemic propafenone is classified as 1C antiarrhythmic agent (Kohlhardt and Seifert 1980;Dukes et al 1984;Tamargo and Delgado 1985;Bryson et al 1993) with a weak calcium antagonistic effect (Ledda et al 1981;Dukes et al 1984;Delgado et al 1991), and a non-selective b-adrenoceptor blocking activity (Ledda et al 1981;Dukes et al 1984;Delgado et al 1985;Groschner et al 1991) which may be clinically relevant in human (Funck-Brentano et al 1990;Stoschitzky et al 1990;Malfatto et al 1993;Kroemer et al 1994), especially in poor metabolizers (Barbey 1991). The (+)-S-enantiomer is the b-adrenoceptor blocking moiety of propafenone (Kroemer et al 1989;Stoschitzky et al 1990;Groschner et al 1991). However, both (R)-and (S)-propafenone exert equal class I antiarrhythmic activity (Stoschitzky et al 1990;Groschner et al 1991;Schreibmayer and Lindner 1992).…”

“…The (+)-S-enantiomer is the b-adrenoceptor blocking moiety of propafenone (Kroemer et al 1989;Stoschitzky et al 1990;Groschner et al 1991). However, both (R)-and (S)-propafenone exert equal class I antiarrhythmic activity (Stoschitzky et al 1990;Groschner et al 1991;Schreibmayer and Lindner 1992). Thus, more specific antiarrhythmic class I therapy with reduction of b-blocking side effects may be attained with optically pure (R)-propafenone hydrochloride instead of the currently used racemic mixture.…”

A Subset of Highly Effective Propafenone-Type Multidrug Resistance Modulators Lacks Effects on Cardiac Action Potential and Mechanical Twitch Parameters of Rat Papillary Muscles

“…In case of MDR-modulating activity, only minor differences between the two enantiomers of propafenone and selected analogs have been seen . In contrast, as for other propanolamines, ␤-blocking activity has been shown to differ for the enantiomers of propafenone (Groschner et al, 1991). However, ␤-blocking effects of the substances were not subject to evaluation in this study, because there was no exogenous or endogenous ␤-activation present in the heart muscle preparations.…”

Electrophysiological effects of diprafenone, a dimethyl congener of propafenone on guinea‐pig ventricular cells

“…Diprafenone was also shown to have P-adrenoceptor blocking activity, which was several times higher than propafenone (Greenberg et al, 1989;Groschner et al, 1991). These findings suggest that diprafenone, like propafenone, possesses Class-I as well as Class-II antiarrhythmic actions (Vaughan Williams, 1984).…”

“…In vitro experiments in guinea-pig ventricular muscles have shown that diprafenone reduces the maximum upstroke velocity ( of the action potential without affecting the resting membrane potential, and that the Jma inhibition is enhanced in a frequency-dependent manner (Kohlhardt & Seifert, 1983;Kohlhardt & Fichtner 1988a). Diprafenone was also shown to have P-adrenoceptor blocking activity, which was several times higher than propafenone (Greenberg et al, 1989;Groschner et al, 1991). These findings suggest that diprafenone, like propafenone, possesses Class-I as well as Class-II antiarrhythmic actions (Vaughan Williams, 1984).…”