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Open AccessArticle

Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes

1
Department of Pharmacy, Health and Nutritional Sciences, DoE 2018–2022, University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy
2
Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, Profesor García González 2, 41071 Seville, Spain
3
Department of Biotechnology, Chemistry and Pharmacy, DoE 2018–2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
4
Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy
5
Epitech Group SpA, 35030 Saccolongo (PD), Italy
6
Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy
7
Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND)-Université Laval, Québec City, QC G1V 0A6, Canada
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Antonella Brizzi and Luciano De Petrocellis are joint senior authors.
Mar. Drugs 2020, 18(10), 519; https://doi.org/10.3390/md18100519
Received: 3 September 2020 / Revised: 12 October 2020 / Accepted: 14 October 2020 / Published: 18 October 2020
Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators. View Full-Text
Keywords: labdane scaffold; bioactive diterpenes; sclareolide; structure-activity relationships; TRPV4 channel; amides/esters; COVID-19; SARS-CoV-2 labdane scaffold; bioactive diterpenes; sclareolide; structure-activity relationships; TRPV4 channel; amides/esters; COVID-19; SARS-CoV-2
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MDPI and ACS Style

Mazzotta, S.; Carullo, G.; Schiano Moriello, A.; Amodeo, P.; Di Marzo, V.; Vega-Holm, M.; Vitale, R.M.; Aiello, F.; Brizzi, A.; De Petrocellis, L. Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes. Mar. Drugs 2020, 18, 519.

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