Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257

Abstract

The effects of the two isomers, (+)-S 16257 and (-)-S 16260, of a new bradycardic agent, (+/-)-S 15544 (7,8-dimethoxy 3-[3-[[(4.5-dimethoxybenzocyclobutan-1-yl)methyl] methylamino]propyl]1,3,4,5-tetrahydro-2H-3-benzazepin-2-one), were compared in vitro and in vivo on cardiac spontaneous rate and repolarization time. In the isolated rabbit sino-atrial node, the three compounds (3 microM) were equi-effective to reduce the action potential firing rate. In anesthetized pigs, both isomers (0.03, 0.1, 0.3 and 1 mg kg(-1) i.v.) were equipotent to reduce heart rate. For all compounds, the negative chronotropic effect resulted from a reduction in the slope of diastolic depolarization of pacemaker cells. In sino-atrial node cells, (-)-S 16260 (3 microM) increased action potential duration while (+)-S 16257 had a smaller effect. In driven guinea-pig papillary muscles exposed to increasing concentrations of compounds (0.1 to 10 microM) a small prolongation of action potential duration was observed. This prolongation was more marked in rabbit Purkinje fibers stimulated at a low rate. In all cardiac preparations the highest prolongation was observed with (-)-S 16260. In vivo, (-)-S 16260 prolonged QTc at the two highest doses tested while (+)-S 16257 had no effect. In conclusion, resolution of (+/-)-S 15544 into its two enantiomers yielded compounds with the same bradycardic effects. Of the isomers, (+)-S 16257 has an increased specificity with minimal direct effect on action potential repolarization.