Abstract
A series of zatebradine analogues, differing in the basic moiety and in the methylene spacer, have been synthesized; their negative chronotropic activity has been determined in guinea pig atria. The most active compounds have been studied for their blocking properties on the hyperpolarization-activated current I f (which is one of the main currents underlying automatic activity in the sinus node) measured on ventricular myocytes of old spontaneously-hypertensive rats (SHR) by means of the patch-clamp technique. The majority of the substances were able to block I f, with one of them ( 15) being slightly more potent than zatebradine. Surprisingly one analogue ( 6), while showing good negative chronotropic activity, was found to inhibit I f only at high concentration and to markedly reduce outward currents, suggesting for this substance a different mechanism of action responsible for the negative chronotropic effect.
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