Pharmacological characterization of the anandamide cyclooxygenase metabolite

Ruth Alexandra Ross, Susan Craib, Lesley Ann Stevenson, Roger Guy Pertwee, A. Henderson, J. Toole, H. C. Ellington

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Abstract

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 EP1, EP2, EP3, and EP4 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 (EP3 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 muM PGE(2) 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 muM) prevented the contractions induced by both compounds. In the presence of 10 muM 8-chlorodibenz[b,f][1,4]oxazepine10(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 (EP2 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 (EP4 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 muM 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.

Original languageEnglish
Pages (from-to)900-907
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume301
Issue number3
DOIs
Publication statusPublished - 1 Jun 2002

Keywords

  • DEPENDENT PROTEIN-KINASE
  • ACID AMIDE HYDROLASE
  • PROSTANOID RECEPTORS
  • SUBTYPES
  • ANALOGS
  • AGONIST

Cite this

Pharmacological characterization of the anandamide cyclooxygenase metabolite. / Ross, Ruth Alexandra; Craib, Susan; Stevenson, Lesley Ann; Pertwee, Roger Guy; Henderson, A.; Toole, J.; Ellington, H. C.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 301, No. 3, 01.06.2002, p. 900-907.

Research output: Contribution to journalArticle

Ross, Ruth Alexandra ; Craib, Susan ; Stevenson, Lesley Ann ; Pertwee, Roger Guy ; Henderson, A. ; Toole, J. ; Ellington, H. C. / Pharmacological characterization of the anandamide cyclooxygenase metabolite. In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 301, No. 3. pp. 900-907.
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AU - Ross, Ruth Alexandra

AU - Craib, Susan

AU - Stevenson, Lesley Ann

AU - Pertwee, Roger Guy

AU - Henderson, A.

AU - Toole, J.

AU - Ellington, H. C.

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N2 - 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 EP1, EP2, EP3, and EP4 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 (EP3 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 muM PGE(2) 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 muM) prevented the contractions induced by both compounds. In the presence of 10 muM 8-chlorodibenz[b,f][1,4]oxazepine10(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 (EP2 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 (EP4 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 muM 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.

AB - 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 EP1, EP2, EP3, and EP4 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 (EP3 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 muM PGE(2) 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 muM) prevented the contractions induced by both compounds. In the presence of 10 muM 8-chlorodibenz[b,f][1,4]oxazepine10(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 (EP2 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 (EP4 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 muM 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.

KW - DEPENDENT PROTEIN-KINASE

KW - ACID AMIDE HYDROLASE

KW - PROSTANOID RECEPTORS

KW - SUBTYPES

KW - ANALOGS

KW - AGONIST

U2 - 10.1124/jpet.301.3.900

DO - 10.1124/jpet.301.3.900

M3 - Article

VL - 301

SP - 900

EP - 907

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -