Indole-2-Carboxamide as an Effective Scaffold for the Design of New TRPV1 Agonists

Due to its central role in pain, inflammation, and related disorders, the Transient Receptor Potential (TPR) Vanilloid Type-1 (TRPV1) ion channel represents an attractive target for the development of novel antinociceptive and anti-inflammatory agents. Capsaicin, the natural component of chili peppers, is one of the most investigated agonists of this receptor. Several modifications of its structure have been attempted, aiming at finding TRPV1 agonists with improved characteristics, but, to date, no capsaicin-derived agents have reached the market. Based on our previous knowledge of the design and synthesis of TRPV1 agonists, in this paper we propose two small series of indole-2-carboxamides as novel and selective agonists for this ion channel. The newly developed compounds have been structurally characterized and tested in vitro for their ability to modulate TRPV1, in terms of efficacy, potency (EC50), and desensitization (IC50) properties. For the most promising derivatives, selectivity over the TRP ankyrin-1 (TRPA1) channel has been reported. From our study, compound 6g arose as a promising candidate for further evaluation, also in correlation with its in silico-predicted drug-like properties. © 2025 by the authors.