Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics

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• 作者：Yin Chen ; Songlin Wang ; Xiangqing Xu ; Xin Liu ; Minquan Yu ; Song Zhao ; Shicheng Liu ; Yinli Qiu ; Tan Zhang ; Bi-Feng Liu ; Guisen Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4671-4690
• 全文大小：791K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D₂, D₃, and serotonin 5-HT_1A and 5-HT_2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors. Moreover, it possesses low affinity for 5-HT_2C and H₁ receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.