A Novel and Selective Nociceptin Receptor (NOP) Agonist (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (AT-312) Decreases Acquisition of Ethanol-Induced Conditioned Place Preference in Mice.
A Novel and Selective Nociceptin Receptor (NOP) Agonist (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (AT-312) Decreases Acquisition of Ethanol-Induced Conditioned Place Preference in Mice.
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新型选择性伤害感受肽受体 (NOP) 激动剂 (1-(1-((顺)-4-异丙基环己基)哌啶-4-基)-1H-吲哚-2-基)甲醇 (AT-312) 减少乙醇的获取
DOI：
10.1111/acer.13575
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Lutfy,Kabirullah
中科院分区：
文献类型：
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作者：
Zaveri,NurulainT;Marquez,PaulV;Meyer,MichaelE;Polgar,WillmaE;Hamid,Abdul;Lutfy,Kabirullah
背景Nociceptin/Nociceptin FQ是阿片受体样受体（也称为NOP或nociceptin receptor）的内源性肽激动剂，已被证明可阻断乙醇（EtOH）诱导的条件性位置偏爱（CPP）的获得和表达。在这里，我们报告了一种新型小分子NOP配体AT-312（1-（1-（（顺式）-4-异丙基环己基）哌啶-4-基）-1H-吲哚-2-基）甲醇）在体外受体结合和GTPγS功能测定中的表征。然后，我们使用CPP范式研究了AT-312对小鼠中EtOH奖励作用的影响。此外，使用缺乏NOP受体的小鼠及其野生型对照，我们还检查了NOP在AT-312作用中的参与。在CPP paradigm.MethodsFemale小鼠缺乏NOP和/或其野生型对照接受条件反射在存在或不存在的NOP激动剂[AT-312]（1，3，和10 mg/kg）或对照NOP激动剂SCH 221510（10 mg/kg）]，随后连续3天给予生理盐水/EtOH（每日两次），并在第二天在无药物状态下检测CPP。结果我们的体外数据表明，AT-312是一种高亲和力，选择性NOP完全激动剂，对μ阿片受体的选择性为17倍，对κ阿片受体的选择性>200倍。我们的体内研究结果表明，与溶剂处理对照组相比，AT-312在最低剂量（1 mg/kg）下降低EtOH CPP，但在较高剂量（3或10 mg/kg）下完全消除EtOH CPP。AT-312（3 mg/kg）未改变缺乏NOP的小鼠中EtOH诱导的CPP，证实AT-312通过其对NOP受体的作用降低EtOH CPP。AT-312（3 mg/kg）单独给药时未诱导奖赏或厌恶，表明新型小分子NOP激动剂通过NOP受体阻断EtOH诱导的CPP显示出疗效。ConclusionsTogether，这些数据表明，小分子NOP激动剂具有降低酒精奖赏的潜力，可能有希望作为治疗酒精成瘾的药物。
BackgroundNociceptin/orphanin FQ, the endogenous peptide agonist for the opioid receptor‐like receptor (also known as NOP or the nociceptin receptor), has been shown to block the acquisition and expression of ethanol (EtOH)‐induced conditioned place preference (CPP). Here, we report the characterization of a novel small‐molecule NOP ligand AT‐312 (1‐(1‐((cis)‐4‐isopropylcyclohexyl)piperidin‐4‐yl)‐1H‐indol‐2‐yl)methanol) in receptor binding and GTPγS functional assays in vitro. We then investigated the effect of AT‐312 on the rewarding action of EtOH in mice using the CPP paradigm. Further, using mice lacking the NOP receptor and their wild‐type controls, we also examined the involvement of NOP in the effect of AT‐312. Motivational effects of AT‐312 alone were also assessed in the CPP paradigm.MethodsFemale mice lacking NOP and/or their wild‐type controls received conditioning in the presence or absence of the NOP agonist [AT‐312 (1, 3, and 10 mg/kg) or the control NOP agonist SCH221510 (10 mg/kg)] followed by saline/EtOH for 3 consecutive days (twice daily) and tested for CPP in a drug‐free state on the next day.ResultsOur in vitro data showed that AT‐312 is a high‐affinity, selective NOP full agonist with 17‐fold selectivity over the mu opioid receptor and >200‐fold selectivity over the kappa opioid receptor. The results of our in vivo studies showed that AT‐312 reduced EtOH CPP at the lowest dose (1 mg/kg) tested but completely abolished EtOH CPP at higher doses (3 or 10 mg/kg) compared to their vehicle‐treated control group. AT‐312 (3 mg/kg) did not alter EtOH‐induced CPP in mice lacking NOP, confirming that AT‐312 reduced EtOH CPP through its action at the NOP receptor. AT‐312 (3 mg/kg) did not induce reward or aversion when administered alone, showing that the novel small‐molecule NOP agonist shows efficacy in blocking EtOH‐induced CPP via the NOP receptor.ConclusionsTogether, these data suggest that small‐molecule NOP agonists have the potential to reduce alcohol reward and may be promising as medications to treat alcohol addiction.