Structure鈥揊unctional Selectivity Relationship Studies of 尾-Arrestin-Biased Dopamine D2 Receptor Agonists

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• 作者：Xin Chen ; Maria F. Sassano ; Lianyou Zheng ; Vincent Setola ; Meng Chen ; Xu Bai ; Stephen V. Frye ; William C. Wetsel ; Bryan L. Roth ; Jian Jin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7141-7153
• 全文大小：590K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: 鈥渟tructure鈥揻unctional selectivity relationships鈥?(SFSR). We recently disclosed the first 尾-arrestin-biased dopamine D₂ receptor (D₂R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these 尾-arrestin-biased D₂R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.