Arachidonoyl ethanolamide (AEA) was the first endogenous cannabinoid to be isolated and characterized as an agonist acting on the same receptors (CB1 and CB2) as tetrahydrocannabinols (THC).1,2 Since that time, a number of related endocannabinoids have been isolated, most notably 2-arachidonoyl glycerol (2-AG).3 O-Arachidonoyl ethanolamine hydrochloride (O-AEA) is a recently isolated constituent of human and rat brain wherein the ethanolamine moiety is attached "backwards", as an ester instead of an amide, as in AEA.1,2,4 O-AEA has mixed agonist/antagonist activity at the CB1 receptor and does not appear to be the native endogenous cannabinoid agonist at this receptor. This is in keeping with other observations that 2-AG is the primary endogenous CB1 receptor ligand.5
References
1. Devane, W.A., Hanus, L., Breuer, A., et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090), 1946-1949 (1992).
2. Felder, C.C., Briley, E.M., Axelrod, J., et al. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc. Natl. Acad. Sci. U.S.A. 90(16), 7656-7660 (1993).
3. Sugiura, T., Kodaka, T., Kondo, S., et al. Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor• Structural requirements for triggering a Ca2+ transient in NG108-15 cells. J. Biochem. 122(4), 890-895 (1997).
4. Porter, A.C., Sauer, J.M., Knierman, M.D., et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. Journal of Pharmacology and Experimental Therapeutics 301(3), 1020-1024 (2002).
5. Sugiura, T., Kodaka, T., Nakane, S., et al. Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J. Biol. Chem. 274(5), 2794-2801 (1999).