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 7 as a Ca(V)1.2 channel blocker and a K(Ca)1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the Ca(V)1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the Ca(V)1.2 channel blockade and K(Ca)1.1 channel stimulation produced by 7. Finally, 7 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. © 2022 by the authors.

Carullo, G., Saponara, S., Ahmed, A., Gorelli, B., Mazzotta, S., Trezza, A., et al. (2022). Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels. MARINE DRUGS, 20(8), 1-22 [10.3390/md20080515].

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

Carullo, Gabriele;Saponara, Simona;Ahmed, Amer;Gorelli, Beatrice;Trezza, Alfonso;Gianibbi, Beatrice;Campiani, Giuseppe;Fusi, Fabio
;
2022-01-01

Abstract

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 7 as a Ca(V)1.2 channel blocker and a K(Ca)1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the Ca(V)1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the Ca(V)1.2 channel blockade and K(Ca)1.1 channel stimulation produced by 7. Finally, 7 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. © 2022 by the authors.
2022
Carullo, G., Saponara, S., Ahmed, A., Gorelli, B., Mazzotta, S., Trezza, A., et al. (2022). Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels. MARINE DRUGS, 20(8), 1-22 [10.3390/md20080515].
File in questo prodotto:
File Dimensione Formato  
53) Novel Labdane Diterpenes Based Synthetic Derivatives identification of a bifunctional vasodilator that inhibits CaV1 2 and stimulates KCa1 1 channels.pdf

accesso aperto

Descrizione: Articolo
Tipologia: PDF editoriale
Licenza: Creative commons
Dimensione 4.79 MB
Formato Adobe PDF
4.79 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1215524