RT Journal Article
T1 PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: evaluation of a novel oleic acid conjugate in preclinical rat models
A1 Alén Fariñas, Francisco
A1 Decara, Juan
A1 Brunori, Gloria
A1 You, Zhi-Bing
A1 Buhler, Kora Mareen Katharina
A1 López Moreno, José Antonio
A1 Cippitelli, Andrea
A1 Pavon, Francisco Javier
A1 Suárez, Juan
A1 Gardner, Eliot
A1 de la Torre, Rafael
A1 Ciccocioppo, Roberto
A1 Serrano, Antonia
A1 Rodríguez de Fonseca, Fernando
AB 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 drugsmight 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 administrationof 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.
PB Elsevier
SN 0006-2952
YR 2018
FD 2018-10-05
LK https://hdl.handle.net/20.500.14352/97783
UL https://hdl.handle.net/20.500.14352/97783
LA eng
NO Francisco Alen, Juan Decara, Gloria Brunori, Zhi-Bing You, Kora-Mareen Bühler, Jose Antonio López-Moreno, Andrea Cippitelli, Francisco Javier Pavon, Juan Suárez, Eliot L. Gardner, Rafael de la Torre, Roberto Ciccocioppo, Antonia Serrano, Fernando Rodríguez de Fonseca, PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models, Biochemical Pharmacology, Volume 157, 2018, Pages 235-243, ISSN 0006-2952, https://doi.org/10.1016/j.bcp.2018.09.008.
DS Docta Complutense
RD 3 jul 2024