Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3 Receptor Antagonists

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• 作者：Jianyong Chen ; Beth Levant ; Cheng Jiang ; Thomas M. Keck ; Amy Hauck Newman ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4962-4968
• 全文大小：309K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

We report a class of potent and selective dopamine D₃ receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D₃ receptor (K_i = 12.8 渭M), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K_i values of 2.7 and 2.8 nM at the rat and human dopamine D₃ receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D₂ receptors. Evaluation in a 尾-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D₃ receptor.