Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

Selected potent TRPV1 agonists (1–6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with Ki (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.