Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing

Chronic pain determines a substantial burden on individuals, employers, healthcare systems, and society. Most of the affected patients report dissatisfaction with currently available treatments. There are only a few and poor therapeutic options—some therapeutic agents are an outgrowth of drugs targeting acute pain, while others have several serious side effects. One of the primary degradative enzymes for endocannabinoids, fatty acid amide hydrolase (FAAH) attracted attention as a significant molecular target for developing new therapies for neuropsychiatric and neurological diseases, including chronic pain. Using chemical graph mining, quantitative structure–activity relationship (QSAR) modeling, and molecular docking techniques we developed a multi-step screening protocol to identify repurposable drugs as FAAH inhibitors. After screening the DrugBank database using our protocol, 273 structures were selected, with five already approved drugs, montelukast, repaglinide, revefenacin, raloxifene, and buclizine emerging as the most promising repurposable agents for treating chronic pain. Molecular docking studies indicated that the selected compounds interact with the enzyme mostly non-covalently (except for revefenacin) through shape complementarity to the large substrate-binding pocket in the active site. A molecular dynamics simulation was employed for montelukast and revealed stable interactions with the enzyme. The biological activity of the selected compounds should be further confirmed by employing in vitro and in vivo studies.

Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors

This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure–activity relationship based on the ligand–enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules’ binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.

A commentary on drug safety and genomics: Promising new agents may require expansion of guidelines for subject screening in clinical trials

The fatty acid amide hydrolase (FAAH) inhibitors likely represent a novel therapeutic yet complex target with the potential to impact various disease processes that present significant unmet medical needs. Despite a history of significant adverse events and still ill-defined risks associated with FAAH inactivation, potential clinical results of FAAH inhibitors for the management of human diseases suggest strongly that the research not be abandoned. In the present commentary we argue that the way to move forward safely and effectively may lie in universal expansion of clinical trials guidelines and toxicology protocols to include targeted genomic screening of clinical trial subjects. Generalization to the safety testing of many new pharmaceutical agents may be the silver lining of an otherwise dark cloud.

Beyond the Canonical Endocannabinoid System. A Screening of PPAR Ligands as FAAH Inhibitors

In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer’s disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field.

Psychosocial and Biological Aspects of Synthetic and Natural FAAH Inhibitors

Molecular engineers are studying FAAH as a target for pharmaceuticals as controlling levels of FAAH may produce some of the same health effects that excite clinicians about the potential for phytocannabinoid-based medicines. Synthetic cannabinoids work by flooding the system with molecules structurally similar to THC and other phytocannabinoids. Medicines that inhibit the body’s production of FAAH are theorized to have a similar effect by maximizing the concentration of deficient endocannabinoids in the nervous system. Technological limitations coupled with a suppression of research of biologic cannabinoids at many major research universities have limited our understanding of the endocannabinoid system. Questions still need to be answered to provide a comprehensive comparison of biologic with synthetic FAAH inhibitors. Advancement and research aimed at understanding of endogenous and exogenous cannabinoids, and particularly the medicinal properties of the Trans-Δ⁹-Tetrahydrocannabinol (THC) molecule and its endocannabinoid equivalent anandamide are hindered by prohibitive restrictions resulting from the Food and Drug Administration (FDA), Drug Enforcement Administration (DEA), National Institute of Health (NIH), and the National Institute on Drug Abuse (NIDA). The mission statements of each of these entities effectively integrate to ensure research and utilization of the medicinal properties of THC will be nearly impossible to attain.

3D-QSAR on a Series of Pyrimidinyl-Piperazine-Carboxamides Based Fatty Acid Amide Hydrolase (FAAH) Inhibitors as a Useful Tool to Obtain Novel Endocannabinoid Enhancers

Fatty Acid Amide Hydrolase (FAAH) is one of the enzymes responsible of endocannabinoids metabolism. The inhibition of FAAH is a useful and indirect strategy to raise endogenous cannabinoid concentrations, which would be useful for the treatment of various pathological processes in which cannabinoid concentrations are lowered. In the present work, we present an extensive 3D-QSAR/CoMSIA study on a series of 90 irreversible inhibitors of FAAH of pyrimidinyl-piperazine-carboxamide structure. The final model obtained was extensively validated (q2 = 0.734; r2test = 0.966; r2m = 0.723), and based on the information derived from the contour maps we reported a series of 10 new compounds designed as powerful FAAH inhibitors (pIC50 of the best-proposed compounds = 12.196; 12.416).