Discovery, Optimization, and Characterization of Novel D2 Dopamine Receptor Selective Antagonists

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• 作者：Jingbo Xiao ; R. Benjamin Free ; Elena Barnaeva ; Jennie L. Conroy ; Trevor Doyle ; Brittney Miller ; Marthe Bryant-Genevier ; Mercedes K. Taylor ; Xin Hu ; Andr茅s E. Dulcey ; Noel Southall ; Marc Ferrer ; Steve Titus ; Wei Zheng ; David R. Sibley ; Juan J. Marugan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3450-3463
• 全文大小：808K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders.