Keywords :
TRPV1 channel modulators; 1-(2,2-dimethylchroman-4-yl)-3-phenylureas; 1-(2,2-dimethylchroman-4-yl)-3-phenylthioureas; pain; TRPV1
Abstract :
[en] The urgent need for safer analgesics, highlighted by the limitations and adverse effects associated with opioid therapies, has intensified the search for alternative strategies in pain management. Among emerging targets, the transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in nociception. Activated by heat, acidic environments, and inflammatory mediators, TRPV1 induces neuronal depolarization and promotes the release of algogenic substances, thereby contributing to pain signal transmission.
Several TRPV1-targeting strategies have been explored, including both agonists and antagonists. Agonists such as capsaicin can induce nociceptor desensitization, while antagonists directly inhibit nociceptive signal transmission.
In this context, benzopyran derivatives have emerged as a promising chemical class capable of interacting with key residues within the TRPV1 binding site. Preliminary studies demonstrated the inhibitory activity of selected compounds, supporting this scaffold as a valuable starting point for further optimization.
The present work aims to explore and optimize benzopyran-based modulators through a medicinal chemistry approach combining rational design, chemical synthesis, and biological evaluation. Structure-activity relationship studies were undertaken to investigate the influence of key structural parameters, including the nature of the urea/thiourea linker at position 4 and the different aromatic substitutions on the benzopyran ring as well as on an associated benzene ring. Additional modifications, such as stereochemical considerations, are currently under investigation.
Overall, this work highlights benzopyran derivatives as promising candidates for the development of safer and effective TRPV1-targeted analgesics.
