Submitted on August 18, 2005
Accepted on August 19, 2005
Enzymatic formation of prostamide F2
from anandamide involves a newly identified intermediate metabolite, prostamide H2
Wu Yang, Jinsong Ni, David F. Woodward, Diane D-S Tang-Liu, and Kah-Hiing John Ling
PKDM, Allergan, Inc., Irvine, CA 92612
Corresponding Author: yang_wu{at}allergan.com
Prostaglandin F2a 1-ethanolamide (Prostamide F2a) is a potent ocular hypotensive agent in animals and represents a new class of fatty acid amide compounds. Accumulated evidence indicated anandamide, an endogenous bioactive ligand for cannabinoid receptors, may serve as a common substrate to produce all prostamides including prostamide F2a. Following incubation of anandamide with cyclooxygenase 2(COX-2), the reaction mixture was profiled by HPLC and an intermediate metabolite was discovered and characterized as a cyclic endoperoxide ethanolamide using HPLC tandem mass spectrometry (HPLC-MS/MS). Formation of prostamide F2a was also demonstrated when the intermediate metabolite was isolated and incubated with prostaglandin F synthase. These results suggest that the biosynthesis of prostamide F2a proceeds in two consecutive steps, oxidation of anandamide to form an endoperoxide intermediate by COX-2, and reduction of the endoperoxide intermediate to form prostamide F2a by PGF synthase. This endoperoxide ethanolamide intermediate has been proposed as prostamide H2.
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