N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists

详细信息    查看全文

• 作者：Amy Hauck Newman ; Peter Grundt ; George Cyriac ; Jeffrey R. Deschamps ; Michelle Taylor ; Rakesh Kumar ; David Ho ; Robert R. Luedtke
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2559-2570
• 全文大小：201K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH₃-phenylpiperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure−activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K_i = 1 nM) for D3 and 400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.