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 18l.
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy. Electronic address: l.depetrocellis@icb.cnr.it.
Luciano
L
De Petrocellis
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza-Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy.
Giorgio
G
Ortar
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.
Aniello
A
Schiano Moriello
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, United States.
Eric M
EM
Serum
Department of Chemistry, University of Wisconsin-River Falls, 410 S. Third St., River Falls, WI 54022, United States.
David B
DB
Rusterholz
D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000819:agonists*
D011744:Pyrimidinones; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C490483:icilin
Icilin; TRPM8; TRPV1; Thermo-TRP channels