Evodiamine functions as an agonist for the vanilloid receptor TRPV1.
Evodiamine, a quinozole alkaloid constituent of Evodia rutaecarpa, has been reported previously to induce several responses comparable to capsaicin in animal systems. Here, we characterize evodiamine as an agonist for rat TRPV1 expressed heterologously in CHO cells. Evodiamine bound to rat TRPV1 with a Ki of 5.95 +/- 0.87 microM, as measured by inhibition of [3H] RTX binding (capsaicin, Ki = 1.8 +/- 0.3 microM). Evodiamine was a full agonist for induction of 45Ca2+ uptake, with an EC50 of 856 +/- 43 nM (capsaicin, EC50 = 45 +/- 4 nM) and was competitively antagonized by capsazepine, as revealed by a Schild plot. The pattern of cellular response, as determined by calcium imaging, was similar to that with capsaicin and yielded an EC(50) of 1.03 +/- 0.21 [micro sign]M. Molecular modeling suggested a consistent pattern of overlap between evodiamine and TRPV1 agonists. We conclude that evodiamine represents a novel class of agonists for rat TRPV1, albeit 3-19-fold less potent than capsaicin, and thus represents a new potential class of lead molecules for drug development.
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Building 37, Room 4048, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255, USA. blumberp@dc37a.nci.nih.gov
Larry V
LV
Pearce
Pavel A
PA
Petukhov
Tamas
T
Szabo
Noemi
N
Kedei
Fero
F
Bizik
Alan P
AP
Kozikowski
Peter M
PM
Blumberg
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002413:Cations, Divalent / Q000737:chemistry; D006224:Cricetinae; D004224:Diterpenes / Q000737:chemistry; D008024:Ligands; D008954:Models, Biological; D008968:Molecular Conformation; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism
D002413:Cations, Divalent; D004224:Diterpenes; D008024:Ligands; D010936:Plant Extracts; D011799:Quinazolines; D050916:TRPV Cation Channels; C024353:resiniferatoxin; C049639:evodiamine; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium