Pfizer completed recently a Phase II clinical trial analysing the safety of the FAAH inhibitor PF-04457845 examining pain relief in patients with OA of the knee. Reason for some reflections. FAAH inhibition results in higher intracellular levels of endocannabinoids, such as anandamide and palmitoylethanolamide. The availability of palmitoylethanolamide as dietfood for medical purposes seems to make the inhibition approach somewhat debatable. This the more so, as there are a number of warning signals around that FAAH inhibition might also trigger opposite results as what we aim for. The structure of the FAAH enzyme, residing in membranes here above, developed by Scripps.

In 'PAIN' Volume 152, Issue 5 , Pages 959-960, May 2011 Aron H. Lichtman and Victoria Chapman published an editorial titled 'A FAAH-fetched approach to treat osteoarthritis pain.' In this editorial the authors commented on a preclinical study containing convincing evidence that activation of the endogenous cannabinoid (endocannabinoid) system (ECS) reduces nociception in the rat monosodium iodoactetate (MIA) and spontaneous Dunkin Hartley guinea pig models of osteoarthritis (OA).

They firstly defined the ECS as the biological system consisting of: 'CB1 and CB2 receptors, the naturally occurring ligands anandamide and 2-arachidonylglycerol, and enzymes regulating endocannabinoid biosynthesis and degradation.' The editorial focusses on the irreversible inhibitors of the enzyme FAAH, which degrades the endocannabinoids. Thus this intervention would enhance the endocannabinoid tone, which is the aim.

However, we do not totally agree with their statements, as they ommitted some data in their editorial discussion which seem to us quite critical for the approach via FAAH inhibition. 

Inhibitors of FAAH as analgesic compounds in osteoarthrosis

URB597 can reduce nociception in two different models of OA pain. This is of particular interest, according to the editorial, as this points out the relevance of endocannabinoids in the treatment of osteoarthrotic pain. It is not only the effect of the FAAH inhibitors in these models, supporting the role of endocannabinoids in OA pain. The presence of CB1 and CB2 receptors, as well as the endocannabinoids in synovia of patients with end-stage OA, together with the increased levels of endocannabinoids in the synovial fluid of these patients, all supports the idea that cannabinoid-based medicines may have therapeutic potential for the treatment of OA pain. 

We can only agree with this statement as we treated succesfully in our clinic osteoartrotic pain with the endocannabinoid palmitoylethanolamide.

The preliminary results of the Pfizer trial further arises interest in the question  “Is FAAH or the endogenous cannabinoid system, in general, a viable target to treat OA and other types of pain?” 

Is FAAH a useful target? 

In our clinic we find these issues rather interesting, given our extensive experience treating various painstates with the endocannabinoid palmitoylethanolamide. This endocannabinoid is also a target for FAAH, and thus many of the data we collected on palmitoylethanolamide can be considered as proof of principle that indeed the endocannabinoid system plays a major role in chronic pain states. There are some concerns however. But first let us hear what the authors stated at the end of their paper:

FAAH inhibitors might represent a promising strategy to treat pain syndromes, such as neuropathic/cancer pain, fibromyalgia, and MS. Further insight as to whether FAAH represents a viable target to treat OA-related pain in human patients awaits the publication of the PF-04457845 clinical trial. Regardless of the outcome of this trial, further clinical research is warranted to determine whether FAAH inhibitors reduce the multiple features of pain in conditions sensitive to exogenous cannabinoid treatment.

FAAH inhition might be not such a good idea..

In a recent paper related to the function of FAAH related to the endocannabinoid tone the following remark is important^[1]  

Data from the literature, however, caution on a global inhibition of FAAH or other endocannabinoid-metabolizing enzymes in the brain, as it has been demonstrated that endocannabinoids regulate neuronal activity in certain cerebral regions in a selective, subtle manner (Losonczy et al, 2004; Hentges et al, 2005).

Furthermore, the reported constitutively action of endocannabinoids could be compromised as a result of FAAH inhibition, with unpredictable consequences.

And: 

...recent data warn against the prolonged blockade of FAAH in astrocytes. We have tested the influence of the genetic inactivation of FAAH (FAAH-knock outs) on the response of primary cortical mouse astrocytes cultures when exposed to synthetic fibrils of amyloid 1-42 (Benito et al., submitted). As expected, the addition of this peptide to the cells led to profound changes in the cytokine secretion profile, with increases in selected molecules, such as IL1b, IL6, TNFalpha, CCL2 and CCL5. In addition, the expression of several enzymes known to be involved in neuroinflammation, such as COX-2 and iNOS, were also augmented. 

FAAH inhibition leads to increase of various actors which play a role in inflammation, thus a paradoxical state is induced, one we would like to avoid.  

We also find it quite strange that the massive preclinical literature as well as the various clinical trials on the efficacy and safety of palmitoylethanolamide have not been mentioned at all in the above discussed editorial.

Palmitoylethanolamide on demand synthesis in artritis

In the paper ' Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis' (2008) this graph represents the synthesis on demand in artrosis and artritis of palmitoylethanolamide. ^[2] As we can see the synthesis of the anti-inflammatory endocannabinoid palmitoylethanolamide is in the artritis state higher than in artrosis, corresponding with the higher inflammation-index in artritis.

Jan M. Keppel Hesselink, MD, PhD, april 2011 

Addendum: Scripps Research/Pfizer Team Produces a Potential New Painkiller

In 2003, the Cravatt group began collaborating with Pfizer to pursue, among other goals, development of FAAH inhibitors.  This collaboration led to the discovery of a promising class of inhibitors known as piperidine ureas, which have proven remarkably specific in their binding with FAAH.

"The trick with these compounds, what makes them so special, is that they are actually very unreactive in general," says Cravatt. "It's only with FAAH that they become reactive, so they derive their exquisite selectivity from this remarkable mechanistic synergy."

The piperidine urea class also proved to be extremely long-lasting because the mechanism by which they inhibit FAAH, preventing the enzyme from breaking down anandamide, is irreversible.

Despite attractive selectivity and stability, the best of the initial discoveries, PF-750, was only moderately potent. So, Pfizer made a significant effort to improve the potency and pharmacokinetic properties without decreasing selectivity, and PF-3845 has emerged with many desirable properties.  Professor Raymond Stevens, whose lab at Scripps Research has solved three-dimensional structures relevant to the FAAH work, also joined the collaboration.  His lab solved the crystal structure of the PF-3845 in complex with the FAAH enzyme, which is also disclosed in this paper. 

Initial experiments have shown PF-3845 to be 10 to 20 times more potent than other FAAH inhibitors, and it reduces inflammatory pain in pre-clinical models. 

What compounds Pfizer will choose to pursue as drug candidates is proprietary information, but Cravatt says that PF-3845 should prove to be an invaluable research tool regardless. Because PF-3845 so effectively blocks FAAH activity, the compound will open a number of research possibilities—some for the first time. Its superior pharmacokinetic properties, for instance, will make it possible to reliably study whether or how the effects of FAAH inhibition change over the long term.

Having spent more than a decade studying the endocannabinoid system, Cravatt says it is rewarding to discover a compound that so powerfully controls it. However, he says, the most rewarding side of the work has been the success of the Pfizer partnership. "This is something that never would have been accomplished without such an open and energetic academic-industrial collaboration." 

"This has been an exciting and productive partnership from the very beginning and is a great example of harnessing the strengths of academia and industry to positively impact the drug discovery process," say Kay Ahn and Douglas Johnson, who were the Biology and Chemistry leaders of the FAAH project at Pfizer. 

In addition to Cravatt, Stevens, Ahn, and Johnson, authors on the paper, titled "Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain," are Mauro Mileni, Jonathan Long, Michele McKinney, and Eranthie Weerapana from Scripps Research, and David Beidler, Nalini Sadagopan, Marya Liimatta, Sarah Smith, Scott Lazerwith, Cory Stiff, Satwik Kamtekar, Keshab Bhattacharya, Yanhua Zhang, Stephen Swaney, and Keri Van Becelaere from Pfizer. For more information, see http://www.cell.com/chemistry-biology/abstract/S1074-5521(09)00080-5. 

Source: http://www.scripps.edu/newsandviews/e_20090427/cravatt.html 

Addendum: FAAH, a dimeric intramembrane enzyme

FAAH is a dimer capable of monotopic membrane insertion; it has an active site structure consistent with the capacity for hydrolysis of hydrophobic fatty acid amides and structural features amenable to structure-based drug design.

With our knowledge of the 3-dimensional structure, we are trying to understand how the enzyme works at a basic level and how it might be the basis for potential drug discovery. More recently in a collaboration with Pfizer, the rat enzyme active site has been converted into the human residues allowing for drug development for both the rat and human species. 

Source: http://stevens.scripps.edu/FAAH.html 

Historical References on FAAH

Bracey, M. H. et al. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298, 1793–1796 (2002)

Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76–81 (2003)

Cravatt, B. F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl Acad. Sci. USA 98, 9371–9376 (2001)  

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