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 is a potent, noncompetitive inhibitor of MGL, exhibiting an IC50 of 200 nM for the recombinant rat brain enzyme.[5] It inhibits rat brain fatty acyl amide hydrolase (FAAH) less effectively with an IC50 of 32 µM and binds weakly to the rat CB1 receptor with an IC50 of 3.8 µM. 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.[6] In the recent study URB754 failed to inhibit 2-AG hydrolysis in rat brain preparations and brain FAAH activity was also resistant to URB754.[7]

[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)