新型香豆素衍生物作为潜在非典型抗精神病药物的合成与评价
Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics.
作者信息
Chen Yin, Lan Yu, Wang Songlin, Zhang Heng, Xu Xiangqing, Liu Xin, Yu Minquan, Liu Bi-Feng, Zhang Guisen
机构信息
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
出版信息
Eur J Med Chem. 2014 Mar 3;74:427-39. doi: 10.1016/j.ejmech.2014.01.012. Epub 2014 Jan 15.
In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors, together with a low affinity for H₁ receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine.
在本文中，我们报道了新型潜在抗精神病香豆素衍生物的合成，该衍生物兼具强效多巴胺D₂、D₃以及5-羟色胺5-HT(1A)、5-HT(2A)受体特性。我们阐述了结构活性关系，由此得到了有前景的衍生物：7-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-6-甲基-2,3-二氢环戊[c]色烯-4(1H)-酮27。化合物27独特的药理学特性是对多巴胺D₂、D₃以及5-羟色胺5-HT(1A)、5-HT(2A)受体具有高亲和力，同时对H₁受体具有低亲和力（以降低长期治疗下肥胖的风险）。在动物模型中，化合物27在测试的最高剂量下抑制阿扑吗啡诱导的攀爬行为以及MK-801诱导的多动，且未观察到僵住症。特别地，化合物27比氯氮平更有效。
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