2-Arachidonoyl glycerol (2-AG) is an endogenous agonist of the central cannabinoid (CB₁) receptor.^1,2 It is present at relatively high levels in the central nervous system and is the most abundant molecular species of monoacylglycerol found in rat brain.^2,3 Monoacylglycerol lipase (MGL) hydrolyzes 2-AG to arachidonic acid and glycerol, thereby terminating its biological actions.⁴ URB754 is reported to be a potent, noncompetitive inhibitor of monoacylglycerol lipase (MAGL), exhibiting an IC₅₀ of 200 nM for the recombinant rat brain enzyme.⁵ However, data from other labs indicates that it does not inhibit human recombinant, rat brain, or mouse brain MAGL at concentrations up to 100 µM.^6,7 It inhibits rat brain fatty acyl amide hydrolase (FAAH) with an IC₅₀ of 32 µM and binds weakly to the rat central cannabinoid (CB₁) receptor with an IC₅₀ of 3.8 µM.⁵ It does not inhibit cyclooxygenase-1 (COX-1) or COX-2 at concentrations up to 100 µM.⁵ Inhibition of 2-AG hydrolysis is associated with enhanced stress-induced analgesia and may represent a novel drug target in pain and stress management.⁸

1 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 2794-2801 (1999).

2 Stella, N., Schweitzer, P., Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388 773-778 (1997).

3 Kondo, S., Kondo, H., Nakane, S., et al. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: Identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and -independent mechanisms. FEBS Lett 429 152-156 (1998).

4 Dinh, T.P., Carpenter, D., Leslie, F.M., et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99(16) 10819-10824 (2002).

5 Makara, J.K., Mor, M., Fegley, D., et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 8(9) 1139-1141 (2005).

6 Saario, S.M., Palomäki, V., Lehtonen, M., et al. URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain. Chem Biol 13 811-814 (2006).

7 Vandevoorde, S., Jonsson, K., Labar, G., et al. Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis in vitro. Br J Pharmacol 150 186-191 (2007).

8 Hohmann, A.G., Suplita, R.L., Bolton, N.M., et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435 1108-1112 (2005).

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 2794-2801 (1999).

Kondo, S., Kondo, H., Nakane, S., et al. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: Identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and -independent mechanisms. FEBS Lett 429 152-156 (1998).

Vandevoorde, S., Jonsson, K., Labar, G., et al. Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis in vitro. Br J Pharmacol 150 186-191 (2007).

Saario, S.M., Palomäki, V., Lehtonen, M., et al. URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain. Chem Biol 13 811-814 (2006).

Stella, N., Schweitzer, P., Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388 773-778 (1997).

Makara, J.K., Mor, M., Fegley, D., et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 8(9) 1139-1141 (2005).

Hohmann, A.G., Suplita, R.L., Bolton, N.M., et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435 1108-1112 (2005).

Dinh, T.P., Carpenter, D., Leslie, F.M., et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99(16) 10819-10824 (2002).

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