Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

Abstract

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.

Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators

“…Polypharmacological approaches targeting the ECS have already shown successful results in diverse disease models (Fernández-Fernández et al, 2014;Malek and Starowicz, 2016;Barutta et al, 2017;Lago-Fernandez et al, 2021). However, drug discovery strategies primarily targeting CB2 and TRPV1 have not yet been explored.…”

“…The ECS is composed by a variety of receptors including GPCRs, TRP channels, nuclear receptors such as the PPARs (Morales et al, 2017b). Polypharmacological approaches targeting this system have already shown successful results (Fernández-Fernández et al, 2014;Malek and Starowicz, 2016;Barutta et al, 2017;Lago-Fernandez et al, 2021). For instance, a PPARγ-CB2 molecule has entered clinical trials for the treatment of systemic and multiple sclerosis (EHP-101, 2020;Palomares et al, 2018).…”

The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study

“…The result is a positive energy balance, and thus the development of obesity, as evidenced by a significant increase in BMI in the patients’ group over the 5-year follow-up. Extensive research focused on the central and peripheral role of the eECS in the energy balance [ 73 ], and it is convincingly shown that the controlled downregulation of the CB 1 receptors and upregulation of PPAR-α and PPAR-γ are involved in the therapeutic effects exhibited by eCB-s and eCB-like NAEs in the role of the regulation of lipid metabolism and obesity [ 74 , 75 ]. According to interdisciplinary studies, PPAR-γ agonists may reverse the brain energetic signature in SSD and help to restore the bioenergetic abnormalities among a subgroup of patients with cognitive dysfunction [ 76 ], and Wada et al [ 77 ] reported evidence of the causal relationship between the dysfunction of PPAR-α and SSD.…”

A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE)

“…The collected organic portions were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The solid residues were recrystallized from n-hexane (11) or CHCl 3 /n-hexane (5) affording the title compounds. (S)-Methyl-(4-bromophenoxy)-2-phenylpropanoate (S-14).…”