化学
药理学
兴奋剂
孤儿受体
渗透剂(生化)
G蛋白偶联受体
鼻腔给药
自我管理
基因剔除小鼠
部分激动剂
受体
酒
生物化学
医学
有机化学
基因
转录因子
作者
Chunyang Jin,Ann M. Decker,Viren H. Makhijani,Joyce Besheer,Emmanuel Darcq,Brigitte L. Kieffer,Rangan Maitra
标识
DOI:10.1021/acs.jmedchem.8b00566
摘要
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.
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