Structure-activity relationships of the prototypical TRPM8 agonist icilin

A series of structural analogues of the TRPM8 agonist icilin was prepared. The compounds were examined for their ability to exert agonist or antagonist effects in HEK-293 cells expressing the TRPM8 receptor. Most structural modifications of the icilin structure largely met with diminished TRPM8 agonist activity. Cinnamamide 'open-chain' analogs of icilin, however, demonstrated significant antagonistic actions at the TRPM8 receptor. Optimal potency (IC50 = 73 nM) was observed in the 3-iodo derivative 181. (C) 2015 Elsevier Ltd. All rights reserved.