Discovery of a Novel Dopamine D3 Receptor Inhibitor

Chem. J. Chinese Universities ›› 2011, Vol. 32 ›› Issue (8): 1779.

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Discovery of a Novel Dopamine D3 Receptor Inhibitor

DENG Xin-Xian¹, SHEN Qing¹, XU Li-Li¹, XIONG Zi-Jun¹, ZHAO Wei-Li¹, ZHEN Xue-Chu², FU Wei^1*

1. Department of Medicinal Chemistry, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Fudan University, Shanghai 201203, China;
2. State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Received:2011-05-12 Revised:2011-06-13 Online:2011-08-10 Published:2011-07-19
Contact: FU Wei E-mail:weifu@gmail.com
Supported by:
国家自然科学基金(批准号: 20702009)、国家“八六三”计划项目(批准号: 2009AA02Z308)和国家“九七三”计划项目(批准号: 2010CB912601)资助.

Abstract

Abstract: Dopamine D3 receptor regulates the synthesis and release of dopamine in brain. It is implicated in many neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control. It is involved in the pathology of psychotic diseases, such as schizophrenia, Parkinson's disease and drug addiction. It is of great significance to discover novel D3 inhibitors through pharmacophore-based virtual screening for the development of anti-psychotic drugs. In this study, we employed the latest discovered high-resolution crystal structure of human D3 receptor to conduct active-site-analysis, build the receptor-based pharmacophore model and screen the Asinex GOLD Collection database. 7 hits were purchased and tested by pharmacological experiments. A novel inhibitor 04932482 with a high activity against D3 receptor was obtained[Ki=(806.75±34.58) nmol/L]. The structure analysis was conducted and the ligand-receptor interaction was further investigated by docking to guide the structure modification and optimization of compound 04932482.

Key words: Dopamine D3 receptor, Pharmacophore model, Database screening, Inhibitor

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DENG Xin-Xian, SHEN Qing, XU Li-Li, XIONG Zi-Jun, ZHAO Wei-Li, ZHEN Xue-Chu, FU Wei*. Discovery of a Novel Dopamine D3 Receptor Inhibitor[J]. Chem. J. Chinese Universities, 2011, 32(8): 1779.

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Discovery of a Novel Dopamine D3 Receptor Inhibitor

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