A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist 6 not only exhibited potent antagonism of activation of hTRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of rTRPV1 by capsaicin. Further studies demonstrated that antagonist 6 blocked the hypothermic effect of capsaicin in vivo, consistent with its in vitro mechanism, and it showed promising analgesic activity in the formalin animal model.

研究了2-（3-氟-4-甲基亚磺酰氨基苯基）丙酰胺1的一系列A区类似物作为TRPV1拮抗剂。结构-活性关系的分析表明，在3-（或/和5-）位置上的氟基团和在4-位置上的甲基磺酰胺基基团对于辣椒素激活TRPV1的拮抗作用是最佳的。最有效的拮抗剂6不仅显示出辣椒素激活h TRPV1的强烈拮抗作用，低pH值和升高的温度，而且显示出辣椒素激活r TRPV1的强烈拮抗作用。进一步的研究表明，拮抗剂6阻断了辣椒素在体内的降温作用，这与其抑制作用一致。体外机制，它在福尔马林动物模型中显示出有希望的镇痛活性。