The discovery of the cannabis receptors CB1 and CB2 and the subsequent discovery of anandamide (N-arachidonoylethanolamine), the first endogenous agonist of both receptors, provided a rationale for the known analgesic properties of Cannabis sativa. Anandamide is rapidly hydrolyzed and inactivated by the serine hydrolase, fatty acid amide hydrolase (FAAH), leading to the hypothesis that inhibition of FAAH would be an effective analgesic strategy. Writing in the journal Chemistry & Biology, scientists at the Scripps Research Institute and Pfizer Inc. have now described the discovery of PF-3845, a highly efficacious and selective inhibitor of FAAH. Mechanistic and structural studies confirmed that PF-3845 acts as a covalent inhibitor and carbamylates the active site serine of FAAH. 
Initial experiments showed that PF-3845 is 10 to 20 times more potent than other FAAH inhibitors and has superior pharmacokinetic properties. In animal studies, PF-3845 raised brain anandamide levels for up to 24 hours and produced a significant cannabinoid receptor-dependent reduction in inflammatory pain. 
Even if PF-3845 is not itself progressed to the clinic, the team believe that it will be a valuable pharmacological tool for further in vivo characterization of the endocannabinoid system.
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