Discovery of nonpungent Transient Receptor Potential Vanilloid (TRPV1) agonist antedrugs for treatment of dysphagia.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel that functions as a cellular sensor for heat and chemical stimuli, such as vanilloids. In recent years, TRPV1 has gained attention as a therapeutic target for treating dysphagia, with both preclinical and clinical trials utilizing capsaicin, a member of the vanilloid family. However, TRPV1 agonists often have pronounced irritant properties and may potentially induce hypothermia upon systemic exposure. Here, we describe the synthesis and characterization of a series of nonpungent TRPV1 agonists with antedrug properties. The discovered compounds exhibit similar agonistic properties to capsaicin, while demonstrating low irritancy in animal models and showing no systemic exposure when administered orally. As these compounds selectively act within the oral cavity without causing a sensation of spiciness, they offer a useful alternative to address the challenges associated with TRPV1 agonists as therapeutic agents for improving dysphagia.