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 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.