Bioorganic & Medicinal Chemistry 2005-02-15

Design, synthesis and preliminary biological evaluation of zatebradine analogues as potential blockers of the hyperpolarization-activated current.

Maria Novella Romanelli, Elisabetta Cerbai, Silvia Dei, Luca Guandalini, Cecilia Martelli, Elisabetta Martini, Serena Scapecchi, Elisabetta Teodori, Alessandro Mugelli

Index: Bioorg. Med. Chem. 13(4) , 1211-20, (2005)

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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 If (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 If, 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 If 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.