Structure-activity relationships of the prototypical TRPM8 agonist icilin

  • Bioorg Med Chem Lett. 2015 Jun 1;25(11):2285-90. doi: 10.1016/j.bmcl.2015.04.032.
Luciano De Petrocellis  1 ,  Giorgio Ortar  2 ,  Aniello Schiano Moriello  3 ,  Eric M Serum  4 ,  David B Rusterholz  5
Affiliations
  • 1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy. Electronic address: [email protected].
  • 2. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza-Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy.
  • 3. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.
  • 4. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, United States.
  • 5. Department of Chemistry, University of Wisconsin-River Falls, 410 S. Third St., River Falls, WI 54022, United States.
PMID: 25935641 DOI: 10.1016/j.bmcl.2015.04.032
Abstract

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 18l.

Keywords
Icilin; TRPM8; TRPV1; Thermo-TRP channels.