2. Academic Validation
  3. PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models

PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models

  • Biochem Pharmacol. 2018 Nov:157:235-243. doi: 10.1016/j.bcp.2018.09.008.
Francisco Alen 1,  Juan Decara 2,  Gloria Brunori 3,  Zhi-Bing You 4,  Kora-Mareen Bühler 5,  Jose Antonio López-Moreno 5,  Andrea Cippitelli 3,  Francisco Javier Pavon 2,  Juan Suárez 2,  Eliot L Gardner 4,  Rafael de la Torre 6,  Roberto Ciccocioppo 3,  Antonia Serrano 7,  Fernando Rodríguez de Fonseca 8
Affiliations

Affiliations

  • 1 Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, 28224, Spain.
  • 2 Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Spain.
  • 3 School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
  • 4 Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
  • 5 Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, 28224, Spain.
  • 6 Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain.
  • 7 Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Spain. Electronic address: antonia.serrano@ibima.eu.
  • 8 Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, 28224, Spain. Electronic address: fernando.rodriguez@ibima.eu.
PMID: 30195735 DOI: 10.1016/j.bcp.2018.09.008
Abstract

Recent studies have demonstrated the utility of drugs modulating the endogenous cannabinoid system to control excessive alcohol intake. Among them, drugs interacting with acylethanolamide receptors including cannabinoid CB1 receptor antagonists/inverse agonists, Peroxisome Proliferator-activated Receptor alpha (PPARα) agonists or Peroxisome Proliferator-activated Receptor gamma (PPARγ) agonists have demonstrated utility in the reduction of alcohol intake in animal models. However, few studies have addressed the potential utility of combining these classes of drugs, especially because of expected safety problems. In the present work we took the advantage of the availability of two novel dual ligands for these receptors, to test the hypothesis that these types of drugs might reproduce and even improve the pharmacological profile of those drugs interacting with single targets. To this end we tested (R)-3-[(4-Benzyl-2-oxooxazolidin-3-yl)methyl]-N-[4-(dodecylcarbamoyl)phenyl]benzamide (NF 10-360), a dual PPARα/γ agonist, and N-[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA), a dual CB1 receptor antagonist/PPARα Agonist, in animal models of alcohol consumption. Both drugs were effective in reducing alcohol intake and alcohol self-administration, being OLHHA a very potent alcohol intake inhibitor (EC50 0.2 mg/kg). OLHHA also reduced self-administration of the opioid oxycodone. OLHHA actions on alcohol self-administration were replicated in alcohol-preferring Marchigian-Sardinian msP rats. Repeated administration of OLHHA did result neither in tolerance nor in toxicological or deleterious metabolic changes in the liver of msP rats. These data support the feasibility of developing novel dual ligands interacting with cannabinoid targets to treat alcohol use disorder in humans.

Keywords

Alcohol use disorder; Cannabinoid CB1 receptor; Dual ligands; Endocannabinod System; PPARα; PPARγ; Rat; Self-administration.

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