Discovery of Potent Dual PPARα Agonists/CB1 Ligands

Pérez-Fernández, Ruth; Fresno, Nieves; Macías-González, Manuel; Elguero, José; Decara, Juan; Girón, Rocı́o; Rodríguez, Ana Marta Guillén; Martı́n, Marı́a Isabel; Fonseca, Fernando Rodrı́guez de; Goya, Pilar

doi:10.1021/ml200091q

Cited by 14 publications

(10 citation statements)

References 23 publications

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“…While our initial studies were ongoing, McGuinness et al (26) reported that fenofibrate was a near‐full agonist compared with CP55940 in a HEK293‐CB 2 cell line using the PathHunter β‐arrestin recruitment assay, with an EC 50 value of 55 nM, in keeping with our results for fenofibrate in competitive radio‐ligand and GTPγS binding assays. In addition, Perez‐Fernandez et al (27) described a series of compounds combining pharmacophores of fenofibrate and rimonabant with nanomolar affinity for both CB 1 and PPAR‐α, although as these compounds were selective antagonists at the CB 1 receptor in the mouse vas deferens bioassay, it is likely that their CB1 effects were mediated via the rimonabant pharmacophore.…”

Section: Discussionmentioning

confidence: 99%

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

et al. 2014

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Cannabinoids are reported to have actions through peroxisome proliferator-activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB 1 ) or cannabinoid type 2 (CB 2 ) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-a agonist fenofibrate exhibited submicromolar affinity for both receptors (pK i CB 1 , 6.3 6 0.1; CB 2 , 7.7 6 0.1). Functionally, fenofibrate acted as an agonist at the CB 2 receptor (pEC 50 , 7.7 6 0.1) and a partial agonist at the CB 1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [ 3 H]-CP55940 at the CB 1 receptor, (k fast without: 1.2 6 0.2/min; with: 3.8 6 0.1 3 10 22 /min) and decrease the maximal response to CP55940 (R max , 86 6 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB 1 receptors (pEC 50 , 6.0 6 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target.-Priestley, R. S., Nickolls, S. A., Alexander, S. P. H., Kendall, D. A. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate.

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Section: Discussionmentioning

confidence: 99%

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

et al. 2014

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“…Consequently, the development of new drugs with dual activity as ligands for CB 1 and PPAR-α has been reported in recent years ( Alvarado et al . , 2008 ; Pérez-Fernández et al, 2011 ). Recently, we have synthesized and characterized a series of compounds derived from fatty acids conjugated with 3,4-methylenedioxymethamphetamine metabolites as anti-obesity drugs ( Almeida et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Treatment with a novel oleic-acid–dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats

Decara

Pavón

Suárez

et al. 2015

Disease Models &Amp; Mechanisms

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Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg−1) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.

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“…In an effort to obtain dual ligands targeting CB 1 R and PPARα, the diarylpyrazole core of the CB 1 R antagonist/inverse agonist SR141716A (Rimonabant, Figure 1) was fused to the phenoxypropanoate pharmacophore of the fibrates (fenofibrate, PPARα agonist, Figure 1), obtaining the so-called rimonabant fibrates [52]. The most potent compound of this series, 2 (Figure 1), exhibited nanomolar activity as a PPARα agonist in luciferase reporter gene assays and a CB 1 R antagonist in mouse vas deferens contractile response assays.…”

Section: Cb 1 R-pparαmentioning

confidence: 99%

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

Lago-Fernandez¹,

Zarzo-Arias²,

Jagerovic³

et al. 2021

IJMS

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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.

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Discovery of Potent Dual PPARα Agonists/CB1 Ligands

Cited by 14 publications

References 23 publications

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

Treatment with a novel oleic-acid–dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats

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

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