A novel series of benzimidazole NR2B-selective NMDA receptor antagonists

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• 作者：David J. Davies^a ; Matthew Crowe^a ; Nolwenn Lucas^a ; Joanna Quinn^a ; David D. Miller^a ; Sara Pritchard^b ; David Grose^a ; Ezio Bettini^c ; Novella Calcinaghi^c ; Caterina Virginio^c ; Lee Abberley^b ; Paul Goldsmith^b ; Anton D. Michel^b ; Iain P. Chessell^b ; James N.C. Kew^b ; Neil D. Miller^b ; Martin J. Gunthorpe^b ; ^{Martin.Gunthorpe@gmail.com}
• 关键词：NMDA ; NR2B ; Glutamate ; Ion channel ; Depression ; Pain ; Drug discovery
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2620-2623
• 文件大小：533 K

摘要

A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as rong class="boldFont">1rong>. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC₅₀ >7) and good selectivity against the NR2A subunit (pIC₅₀ <4.3) as defined by FLIPR-Ca²⁺ and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression.