Sclareolide-based small molecules, TRPV4/Ca_V1.2 modulators, as new vasodilating agents

Sclareolide is a fragrant sesquiterpene lactone found in Salvia sclarea, used as flavor additive in food. (+)-Sclareolide gained attention due to its versatility, since its lactone ring condensed with a trans-decalin-related homodrimane core can be easily opened and functionalized. Structural similarity between sclareolide and phorbol derivatives or onydecalin A, known TRPV4 modulators, prompted us to evaluate if sclareolide and its derivatives could modulate the activity of this channel. A small but diversified library of derivatives, characterized by the homodrimane backbone bearing flexible tails of different nature and chemical properties at position 1, was synthesized. In particular, the substituent groups, bound to the bicyclic nucleus by either an amide or ester or ether functionality, differ in size, flexibility, and electronic properties. The most interesting compounds were active in the submicromolar range and belong to the homodrimanyl acid amide series, in particular, benzyl and phenylethyl amides. Considering that inappropriate activation of TRPV4 produces acute circulatory collapse associated with endothelial activation/injury, and considering that the role of TRPV4 is confused, we investigated the best performing compounds as vasodilators in rat myocytes. The compounds were able to reduce the currents associated with IBa1.2; the mechanism of the interaction between the most intriguing compound and Ca_V1.2 channel was voltage-dependent and antagonized by a channel activator such as Bay K 8644. Furthermore, this compound stabilizes the inactivated state of the channel. Finally, it inhibits the contraction of the aorta rings induced by high potassium with an IC₅₀ comparable to that obtained on the channels.