The cannabinoid receptor (CB1), the G protein-coupled receptor activated by the psychotropic components of marijuana, is an attractive target for the development of anxiety- and pain-reducing therapies. However, exogenously applied cannabinoid agonists have been found to give rather variable effects, and a more specific route to regulating CB1 receptor activity might be to find a way of elevating the levels of the endogenous amidated lipids that activate CB1 receptors. Hence there is interest in targeting the principal degradative enzyme for this group of endogenous CB1 receptor agonists, the membrane-bound fatty acid amide hydrolase (FAAH), and to this end recently published papers now report the high-resolution crystal structure for FAAH, and a new class of potent and selective FAAH inhibitors.

Transgenic mice lacking FAAH have previously been shown to have increased levels of anandamide, the main amidated lipid candidate for the role of the 'endogenous cannabinoid', and to show enhanced CB1 receptor-dependent analgesia (see further reading). Now, in the November 29th issue of Science, Bracey et al. present the 2.8 Å crystal structure of a slightly truncated version of FAAH, complexed with methoxy arachidonyl fluorophosphonate, an active-site-directed inhibitor. The crystallized FAAH variant, despite having the first 29 amino-terminal amino acids deleted, was reported to retain the wild-type enzyme's association with the cell membrane and ability to degrade fatty acid amides. The crystal structure reveals a dimeric enzyme, closely related to malonamidase (MAE2), the other enzyme from the amidase signature family for which a structure has been determined and which hydrolyses malonamide in the nitrogen-fixing bacterium Bradyrhizobium japonicum. Interestingly, the close association found in FAAH between the active site and the cell membrane indicates that membrane-permeable lipids, such as anandamide, might not need to be transported through aqueous cellular compartments in order to be degraded, and therefore that the level of endocannabinoid activity might be controlled by the relative expression levels and placement of FAAH and CB1 receptors in vivo.

Knowing the structure of FAAH may help with the future design of inhibitors, but meanwhile a paper from Daniele Piomelli's group, published online in December's Nature Medicine, reports the discovery of the first selective inhibitors of FAAH. The two most potent compounds in this class of carbamate inhibitors, URB597 and URB532, were able to elicit anxiolytic-like responses in rats without evoking many of the side effects that normally accompany cannabinoid action, and also produced mild anti-nociception in a model of acute pain. FAAH inhibition was shown to result in increased levels not just of anandamide and other amidated lipids that activate CB1 receptors, but also of analogues that act independently of CB1 receptors. So although apparently a new route to the treatment of anxiety by enhancing cannabinoid receptor activation, targeting FAAH also seems likely to affect signalling pathways other than those mediated by CB1 receptors.