Design and synthesis of conformationally restricted capsaicin analogues based in the 1, 3, 4-thiadiazole heterocycle reveal a novel family of transient receptor potential vanilloid 1 (TRPV1) antagonists

4-hydroxy-3-methoxybenzaldehyde was used as starting material to obtain a number of 1, 3, 4-thiadiazole alkylamide derivatives. The pharmacological properties of these conformationally restricted capsaicin analogues were evaluated on HEK-293T cells transiently expressing TRPV1 receptor. By means of a highthroughput calcium imaging assay we find that 1, 3, 4-thiadiazoles (compounds 8-15) act as potent antagonists of the capsaicin receptor, inhibiting both, the capsaicin- and temperature-dependent activation. Docking studies suggested a different binding orientation on the vanilloid binding site when compared with capsaicin analogues, such as 5-iodononivamide. Overall, our studies suggest that 1, 3, 4-thiadiazoles interact with capsaicin's binding region of the receptor, although using a different set of interactions within the vanilloid binding pocket.

1, 3, 4-thiadiazole; AOYSLMGJSODPFL-UHFFFAOYSA-N; Antagonist activity; BSPCBZUBIMXXLE-UHFFFAOYSA-N; CLYGEOIHYUCALV-UHFFFAOYSA-N; CMJXYVMALHZRQM-UHFFFAOYSA-N; Capsaicin analogues; DRG; DYNLINSCGMXBCC-UHFFFAOYSA-N; IITOGCQJPPIAMI-UHFFFAOYSA-N; KWTNWXUICRTCLY-UHFFFAOYSA-N; OSDVZVIOEZHZRA-UHFFFAOYSA-N; Restriction conformational; Rf; TLC; TRPV1 receptor; VMUGFJHHAQTKCY-UHFFFAOYSA-N; VTEBRQCNVDRVGM-UHFFFAOYSA-N; cTRPV1; chicken TRPV1; dorsal root ganglion; rTRPV1; rat TRPV1; retention factor; thin layer chromatography.