Schiano Moriello, Aniello López Chinarro, Silvia Novo Fernández, Olalla Eras, Jordi Amodeo, Pietro Canela-Garayoa, Ramon Vitale, Rosa Maria Marzo, Vincenzo Di Petrocellis, Luciano De Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca<sup>2+</sup> 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. Capsaicin Derivatives;TRPV 2 antagonists;Endogenous Lipids;acid ethanolamides;TRPV subfamily;channel member;Molecular Switch;TRP channel;vanilloid type -2;long-chain capsaicin derivatives;Potent Transient Receptor;physiopathological roles;Hydrophobic Chain;TRPV 2 agonists;Vanilloid Channel 2 Antagonists;TRPV 2 modulators;ligand-based approach 2018-09-03
    https://acs.figshare.com/articles/dataset/Elongation_of_the_Hydrophobic_Chain_as_a_Molecular_Switch_Discovery_of_Capsaicin_Derivatives_and_Endogenous_Lipids_as_Potent_Transient_Receptor_Potential_Vanilloid_Channel_2_Antagonists/7090676
10.1021/acs.jmedchem.8b00734.s002