{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T09:56:45Z","timestamp":1782295005448,"version":"3.54.5"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,13]],"date-time":"2022-08-13T00:00:00Z","timestamp":1660348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>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 CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 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 CaV1.2 channel blockade and KCa1.1 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.<\/jats:p>","DOI":"10.3390\/md20080515","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T03:33:20Z","timestamp":1660534400000},"page":"515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1619-3295","authenticated-orcid":false,"given":"Gabriele","family":"Carullo","sequence":"first","affiliation":[{"name":"Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3831-8669","authenticated-orcid":false,"given":"Simona","family":"Saponara","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-4045","authenticated-orcid":false,"given":"Amer","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Gorelli","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0029-7003","authenticated-orcid":false,"given":"Sarah","family":"Mazzotta","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Trezza","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4946-8398","authenticated-orcid":false,"given":"Beatrice","family":"Gianibbi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Campiani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-8309","authenticated-orcid":false,"given":"Fabio","family":"Fusi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-5582","authenticated-orcid":false,"given":"Francesca","family":"Aiello","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edif. Polifunzionale, 87036 Arcavacata di Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18014","DOI":"10.1038\/nrdp.2018.14","article-title":"Hypertension","volume":"4","author":"Oparil","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2021.627458","article-title":"Review of Natural Resources With Vasodilation: Traditional Medicinal Plants, Natural Products, and Their Mechanism and Clinical Efficacy","volume":"12","author":"Tang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Carullo, G., Mazzotta, S., Koch, A., Hartmann, K.M., Friedrich, O., Gilbert, D.F., Vega-Holm, M., Schneider-Stock, R., and Aiello, F. (2020). 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