Pharmacological characterization of the anandamide cyclooxygenase metabolite: prostaglandin E2 ethanolamide.
Anandamide can be metabolized by cyclooxygenase-2 to produce prostaglandin E(2) (PGE(2)) ethanolamide. The purpose of this study was to investigate the pharmacology of this novel compound. Radioligand binding experiments in membranes from human embryonic kidney cells transfected with PGE(2) receptor subtypes EP(1), EP(2), EP(3), and EP(4) revealed that PGE(2) ethanolamide has pK(i) values of 5.61 +/- 0.1, 6.33 +/- 0.01, 6.70 +/- 0.13, and 6.29 +/- 0.06, respectively, compared with 8.31 +/- 0.16, 9.03 +/- 0.04, 9.34 +/- 0.06, and 9.10 +/- 0.04 for PGE(2). PGE(2) inhibits electrically evoked contractions of the guinea pig vas deferens (EP(3) receptor-mediated), with a pEC(50) value of 9.09 +/- 0.06, compared with that of 7.38 +/- 0.09 for PGE(2) ethanolamide. In the guinea pig trachea, 100 nM PGE(2) and 1 microM PGE(2) ethanolamide produced contractions of 51.8 +/- 10.6 and 38.9 +/- 5.6% (of the histamine E(max)), respectively. The EP(1) receptor antagonist SC-51089 (10 microM) prevented the contractions induced by both compounds. In the presence of 10 microM 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (SC-51089), PGE(2) caused a concentration-related relaxation of histamine-induced contractions of this tissue (EP(2) receptor-mediated), the pEC(50) value being 8.29 +/- 0.17 compared with that of 7.11 +/- 0.18 for PGE(2) ethanolamide. In the rabbit jugular vein, PGE(2) induces relaxation (EP(4) receptor-mediated) with a pEC(50) of 9.35 +/- 0.25, compared with 7.05 +/- 0.4 for PGE(2) ethanolamide. In dorsal root ganglion neurons in culture, 3 microM PGE(2) ethanolamide evoked an increase in intracellular calcium concentration in 21% of small-diameter capsaicin-sensitive neurons. We conclude that this compound is pharmacologically active, however its physiological relevance has yet to be established.
Ross
Ruth A
RA
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK AB25 2ZD. r.ross@abdn.ac.uk
Craib
Susan J
SJ
Stevenson
Lesley A
LA
Pertwee
Roger G
RG
Henderson
Andrea
A
Toole
John
J
Ellington
Heather C
HC
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D053284:Polyunsaturated Alkamides; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D007527:Isoenzymes; D008565:Membrane Proteins; C545635:PTGER1 protein, human; D053284:Polyunsaturated Alkamides; C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C107684:prostaglandin E2 ethanolamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C078814:anandamide