Peroxisome Proliferator Activated Receptor (PPAR) agonists as Fatty Acid Amide Hydrolase (FAAH) inhibitors: screening and preliminary structure-activity relationships

Peroxisome-proliferator activated receptors (PPARs) have been known for some years as part of the cannabinoid signaling system. Indeed, their various receptor subtypes (PPARα, PPARγ and PPARδ) are activated by phytocannabinoids and endocannabinoids alike. This endocannabinoid-mediated activation has multiple downstream effects that could be beneficial in pathological conditions such as Neurodegenerative Disorders and even certain types of cancer [1,2].In order to harness this connection, we have explored the feasibility of coupling PPAR agonism with the enhancement of the endocannabinoid tone. Such anenhancement can be achieved by inhibiting one of the most important enzymes which quickly inactivate endocannabinoids in vivo, namely Fatty Acid Amide Hydrolase (FAAH)[1-3]. With this goal in mind, we have conducted a screening for FAAH inhibitory activity. First, we tested known PPAR agonists that had previously been synthesized in our laboratories; then, we also tested a panel of natural substances and other small phenolic molecules to better investigate the structural requirements for FAAH inhibition.Thus, we tentatively identified a scaffold for the design of dual-acting compounds, whose fascinating potential will be explored in the future.