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dc.contributor.authorSchiano Moriello, Aniello
dc.contributor.authorLópez Chinarro, Silvia
dc.contributor.authorNovo Fernández, Olalla
dc.contributor.authorEras i Joli, Jordi
dc.contributor.authorAmodeo, Pietro
dc.contributor.authorCanela i Garayoa, Ramon
dc.contributor.authorVitale, Rosa Maria
dc.contributor.authorDi Marzo, Vincenzo
dc.contributor.authorDe Petrocellis, Luciano
dc.date.accessioned2018-12-20T12:07:51Z
dc.date.available2019-09-03T22:17:34Z
dc.date.issued2018-09-03
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/10459.1/65384
dc.description.abstractThe transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.
dc.description.sponsorshipWe gratefully acknowledge financial support from Universitat de Lleida, Ministerio de Educación, Cultura y Deporte and Banco Santander (Programa UdL-Impuls). The authors are grateful to the Serveis Cientifictècnics (SCT) of the Universitat de Lleida for providing us with spectroscopic and chromatographic facilities. We acknowledge Dr. Alberto Minassi, Dipartimento di Scienze del Farmaco, Universitàdel Piemonte Orientale, Novara, Italy, for the kind gift of olvanil.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1021/acs.jmedchem.8b00734
dc.relation.ispartofJournal of Medicinal Chemistry, 2018, vol. 61, núm. 18, p. 8255-8281
dc.rights(c) American Chemical Society, 2018
dc.titleElongation of the Hydrophobic Chain as a Molecular Switch:Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2018-12-20T12:07:54Z
dc.identifier.idgrec027934
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1021/acs.jmedchem.8b00734


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