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 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 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 E_max), 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.