Discovery and pharmacological characterization of aryl piperazine and piperidine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT_1A partial agonists

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• 作者：David L. Gray ; Wenjian Xu ; Brian M. Campbell ; Amy B. Dounay ; Nancy Barta ; Susan Boroski ; Lynne Denny ; Lori Evans ; Nancy Stratman ; Al Probert
• 关键词：Norepinephrine reuptake inhibitor ; NRI ; 5-HT1A agonist ; NET ; DAT ; SERT ; 5-Hydroxytryptamine 1A ; ADHD ; Depression
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 December 2009
• 年：2009
• 卷：19
• 期：23
• 页码：6604-6607
• 全文大小：363 K

文摘

Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1_A partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT_1A receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1_A partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT_1A in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.