Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes
Articolo
Data di Pubblicazione:
2020
Citazione:
Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes / S. Mazzotta, G. Carullo, A. Schiano Moriello, P. Amodeo, V. Di Marzo, M. Vega-Holm, R.M. Vitale, F. Aiello, A. Brizzi, L. De Petrocellis. - In: MARINE DRUGS. - ISSN 1660-3397. - 18:10(2020), pp. 519.1-519.18. [10.3390/md18100519]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
amides/esters; bioactive diterpenes; COVID-19; labdane scaffold; SARS-CoV-2; sclareolide; structure-activity relationships; TRPV4 channel; Betacoronavirus; COVID-19; Coronavirus Infections; Diterpenes; Gene Expression Regulation; HEK293 Cells; Humans; Inhibitory Concentration 50; Molecular Structure; Pandemics; Pneumonia, Viral; SARS-CoV-2; Structure-Activity Relationship; TRPV Cation Channels; Drug Design
Elenco autori:
S. Mazzotta, G. Carullo, A. Schiano Moriello, P. Amodeo, V. Di Marzo, M. Vega-Holm, R.M. Vitale, F. Aiello, A. Brizzi, L. De Petrocellis
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