Abstract
TRPA1 functions as a ligand‐gated cation channel in sensory neurons and is an important drug discovery target for identification of novel analgesics. We report identification of a novel structural class of ligands reversibly modulating TRPA1 channel function. Using intracellular calcium measurement and whole cell patch clamp recording of HEK293 cells expressing human TRPA1, we characterized the structure‐activity relationships among a group of amino‐triarylmethane analogs. A minimal structural change switched a full agonist to antagonist and small changes in side chain substituents in the same ring greatly altered affinity among antagonists. The agonists, ALGX‐2014 and ALGX‐2015, only elicited TRPA1 currents when applied extracellularly. Their stimulatory effect was blocked by TRPA1 antagonists and unaffected by substituting the three cysteine residues of TRPA1 critical for covalent stimulation by electrophilic agonists, such as AITC and PGJ2, with alanines, suggesting channel activation occurs in a noncovalent manner. This novel class of allosteric agonists and antagonist ligands also interact with other well‐defined TRPA1 ligands and results suggest a highly conserved binding site among TRPA1 and other members of the thermo‐TRP family which may reside in the channel domain.Grant Funding Source: Supported by NIDA grant (DA031516) to JMH and NIDDK grant (DK081654) to MXZ
Published Version
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