Find in Library

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified <b>7</b> as a Ca_V1.2 channel blocker and a K_Ca1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the Ca_V1.2 channel agonist Bay K 8644 suggested that <b>7</b> might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the Ca_V1.2 channel blockade and K_Ca1.1 channel stimulation produced by <b>7</b>. Finally, <b>7</b> reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca²⁺ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.