Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake
Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake
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DOI：
10.1021/acs.jmedchem.8b00566
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发表时间：
2018-08-09
影响因子：
7.3
通讯作者：
Maitra, Rangan
中科院分区：
文献类型：
--
作者：
Jin, Chunyang;Decker, Ann M.;Maitra, Rangan
孤儿G蛋白偶联受体GPR 88在纹状体中高度表达。使用GPR 88敲除小鼠的研究表明，该受体与酒精寻求和饮酒行为有关。迄今为止，由于缺乏适用于体内研究的有效和选择性激动剂，GPR 88活化的生物学效应仍然未知。在这项研究中，我们报告了第一个有效的，选择性的，脑渗透性GPR 88激动剂RTI-13951-33的发现（6）。在体外cAMP功能试验中，RTI-13951-33的EC 50为25 nM，并且在检测的38个GPCR、离子通道和神经递质转运蛋白中没有显著的脱靶活性。与（1 R，2 R）-2-PCCA（2）相比，RTI-13951-33显示出更高的水溶性，并具有良好的行为评估药代动力学特性。最后，RTI-13951-33以剂量依赖性方式显著降低了大鼠的酒精自我给药和酒精摄入量，但对大鼠的运动和蔗糖自我给药无影响。
The orphan G-protein-coupled receptor GPR88 is highly expressed in the striatum. Studies using GPR88 knockout mice have suggested that the receptor is implicated in alcohol seeking and drinking behaviors. To date, the biological effects of GPR88 activation are still unknown due to the lack of a potent and selective agonist appropriate for in vivo investigation. In this study, we report the discovery of the first potent, selective, and brain-penetrant GPR88 agonist RTI-13951-33 (6). RTI-13951-33 exhibited an EC50 of 25 nM in an in vitro cAMP functional assay and had no significant off-target activity at 38 GPCRs, ion channels, and neurotransmitter transporters that were tested. RTI-13951-33 displayed enhanced aqueous solubility compared to (1R,2R)-2-PCCA (2) and had favorable pharmacokinetic properties for behavioral assessment. Finally, RTI-13951-33 significantly reduced alcohol self-administration and alcohol intake in a dose-dependent manner without effects on locomotion and sucrose self-administration in rats when administered intraperitoneally.