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
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DOI：
10.1016/j.bcp.2018.09.008
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发表时间：
2018-11-01
影响因子：
5.8
通讯作者：
Rodriguez de Fonseca, Fernando
中科院分区：
文献类型：
--
作者：
Alen, Francisco;Decara, Juan;Rodriguez de Fonseca, Fernando
最近的研究证明了调节内源性大麻素系统的药物可用于控制过量的酒精摄入。其中，与酰基乙醇酰胺受体相互作用的药物，包括大麻素CB1受体拮抗剂/反向激动剂、过氧化物酶体增殖物激活受体α（PPARα）激动剂或过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，已在动物模型中证明可用于减少酒精摄入量。然而，很少有研究探讨结合这些类别药物的潜在效用，特别是因为预期的安全问题。在目前的工作中，我们利用这些受体的两种新型双配体的可用性，来测试这些类型的药物可能复制甚至改善这些药物与单一靶点相互作用的药理学特征的假设。为此，我们测试了(R)-3-[(4-苄基-2-氧代恶唑烷-3-基)甲基]-N-[4-(十二烷基氨基甲酰基)苯基]苯甲酰胺(NF 10-360)，一种双重PPARα/γ激动剂，和N-[1-(3,4-二羟基苯基)丙-2-基]油酰胺(OLHHA)，一种双重CB1受体拮抗剂/PPAR阿尔法激动剂，在饮酒的动物模型中。这两种药物都能有效减少酒精摄入和酒精自我给药，OLHHA 是一种非常有效的酒精摄入抑制剂（EC50 0.2 mg/kg）。 OLHHA 还减少了阿片类羟考酮的自我给药。 OLHHA 对酒精自我给药的作用在偏好酒精的马尔基吉亚-撒丁岛 mP 大鼠中得到了复制。重复给予 OLHHA 既不会导致 msP 大鼠肝脏的耐受性，也不会导致毒理学或有害的代谢变化。这些数据支持开发与大麻素靶点相互作用的新型双配体来治疗人类酒精使用障碍的可行性。
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 (PPAR alpha) agonists or peroxisome proliferator-activated receptor gamma (PPAR gamma) 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-(dodecylcarbamoyel)phenyl]benzamide (NF 10-360), a dual PPAR alpha/gamma agonist, and N-[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA), a dual CB1 receptor antagonist/PPAR alpha 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.