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

Abstract

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.

Keywords: Alzheimer’s disease; FAAH; PPARs; anandamide; endocannabinoids; inflammation; multitarget.

Figure 1

Molecular structures of the first 12 compounds involved in the screening.

Figure 2

Molecular structures of phenoxyacetic analogues.

Scheme 1

Synthesis of aryloxyacetic analogues: (a) ethyl 2-bromopropanoate or ethyl bromoacetate, NaH, DMF_dry, N₂, 0 °C > 65 °C; (b) H₂, Wilkinson’s catalyst, THF/EtOH, RT; (c) NaOH 2N, THF, RT.

Scheme 2

Synthesis of the intermediate 29e. (a) N-acetylglycine, NaOAc, Ac₂O, 18 h, 110 °C; (b) HCl 3M, 6 h, 100 °C; (c) MeOH (25%), NaOH 0.1M, NaBH₄, 17 h, RT.

Scheme 3

Synthesis of rosmarinic acid derivatives 28–30. (a) Allyl Alcohol, p-TsOH, 11 h, 100 °C; (b) DMAP, EDCI, Trans-cinnamic acid or 3,4-dimethoxycinnamic acid, 24 h, RT; (c) Pd(PPh₃)₄, morpholine, 2 h, RT.

Scheme 4

Synthesis of clovamide derivatives 31–37. (a) DCC, HOBt x H₂O, TEA, THF/CHCl₃, 0 °C→RT; (b) EDCI, HOBt x H₂O, N-Methylmorpholine, DMF/CH₂Cl₂, 0 °C→RT; (c) LiOH x H₂O, THF/H₂O, 0 °C→RT; (d) BBr₃ 1M, CH₂Cl₂.

Figure 3

(A): docking pose of compound 5. (B): molecular superposition with carprofen (yellow carbons).

Figure 4

Docking poses of (R), (A), and (S), (B) enantiomer of compound 14 into the FAAH binding site.

Figure 5

Docking poses of (R), (A), and (S), (B) enantiomer of compound 18 into the FAAH binding site.