URB754

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urb754

2-Arachidonoylglycerol (2-AG) is an endogenous agonist of the central cannabinoid receptor (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.[1,3] Monoacylglycerol lipase (MGL) hydrolyzes 2-AG to arachidonic acid and glycerol, thereby terminating its biological actions.[4] URB754 was originally reported to be a potent, noncompetitive inhibitor of MGL, however recent studies have shown URB754 failed to inhibit recombinant MGL, 2-AG hydrolysis in rat brain preparations, and brain FAAH activity was also resistant to URB754.[7] Some controversy in the field remains regarding the use of this compound.

[edit] References

Stella, N., Schweitzer, P., Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773-778 (1997).
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).
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).
Makara, J.K., Mor, M., Fegley, D., et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nature Neuroscience 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).
Saario, S.M., Palomäki, V., Lehtonen, M., Nevalainen, T., Järvinen, T., Laitinen, J.T. URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain. Chem Biol 13, 811-814 (2006)