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

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.