GE 68 ((Rac.)-1-[3-(Phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol hydrochloride) is structurally related to propafenone, and exerts negative inotropic and negative chronotropic effects similar to the parent drug, but lacks any beta-adrenoceptor blocking activity contrary to propafenone. Thus, the electrophysiological effects of GE 68 were studied in papillary muscles, left atria, Purkinje fibres, sinoatrial nodes and ventricular myocytes of the guinea-pig heart with the intracellular microelectrode technique and the patch-clamp technique in the cell-attached mode. The decrease of the maximum upstroke velocity (Vmax) by GE 68 (1 to 10 microM) was use- and frequency-dependent. Vmax recovered from the use-dependent block with a time constant of 4.1 +/- 0.6 s. In papillary muscles and Purkinje fibres action potential duration was shortened, while it was prolonged in left atria and sinoatrial nodes. Half-maximal steady-state inactivation of the sodium channels was shifted to more negative membrane potentials (control: -91.5 +/- 0.8 mV, 10 microM GE 68: -97.9 +/- 2.5 mV). The peak of the current-voltage relationship and the reversal potential were not changed by GE 68. The amplitude of the unitary current remained unaltered, while open state probability was decreased. The most striking effect of GE 68 was an increase of the number of sweeps without single channel openings (1 microM: 2fold, 10 microM: 6fold). GE 68 also caused a decrease of the mean open times, and an increase of the mean closed times in unmodified and pronase-modified sodium channels. Besides the lack of beta-adrenoceptor blocking activity, data present a faster recovery from the use-dependent block by GE 68 and a lower affinity to inactivated sodium channels compared to the reference drug propafenone, as well as differences in the effect on single channel kinetics.

An improved synthesis of the enantiomers of the new benzofurane-type antiarrhythmic compound 1 is described, which makes use of the enantiomerically pure mbe-lactol. Thus, acylation of the benzofurane 4 with acetic anhydride and subsequent bromination gave the bromoacetyl-derivative 6, which, after reduction with LiAlH4, was protected with mbe-lactol to give a mixture of the diastereomers 8a and 8b. After separation via column chromatography assignment of absolute configuration was carried out using a well-established NMR-method. Reaction with propylamine and cleavage of the protective group gave (R)-1 and (S)-1, respectively. Enantiomeric purity was confirmed using a direct HPLC method with rsp-cyclodextrine as stationary phase. Pharmacological investigations on isolated guinea pig heart muscle preparations showed that GE 68 and its two enantiomers did not significantly differ from each other with regard to their negative inotropic, negative chronotropic, and lack of beta-adrenoceptor blocking action. In contrast, the reference drug propafenone was equally potent in its negative inotropic and chronotropic activity as GE 68, but additionally showed a weak beta-adrenoceptor blocking activity.