Pharmacological Characterization of the Anandamide Cyclooxygenase Metabolite: Prostaglandin E2 Ethanolamide

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Abstract
Anandamide can be metabolized by cyclooxygenase-2 to produce prostaglandin E2 (PGE2) 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 PGE2receptor subtypes EP1, EP2, EP3, and EP4 revealed that PGE2 ethanolamide has pKi 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 PGE2. PGE2 inhibits electrically evoked contractions of the guinea pig vas deferens (EP3 receptor-mediated), with a pEC50 value of 9.09 ± 0.06, compared with that of 7.38 ± 0.09 for PGE2 ethanolamide. In the guinea pig trachea, 100 nM PGE2 and 1 μM PGE2 ethanolamide produced contractions of 51.8 ± 10.6 and 38.9 ± 5.6% (of the histamine Emax), respectively. The EP1 receptor antagonist SC-51089 (10 μM) prevented the contractions induced by both compounds. In the presence of 10 μM 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (SC-51089), PGE2 caused a concentration-related relaxation of histamine-induced contractions of this tissue (EP2 receptor-mediated), the pEC50 value being 8.29 ± 0.17 compared with that of 7.11 ± 0.18 for PGE2 ethanolamide. In the rabbit jugular vein, PGE2 induces relaxation (EP4 receptor-mediated) with a pEC50 of 9.35 ± 0.25, compared with 7.05 ± 0.4 for PGE2 ethanolamide. In dorsal root ganglion neurons in culture, 3 μM PGE2 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.

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