Note: Postdoctoral recruitment information is available at the end of the article
GPCR is one of the most important drug target families. More than 30% of small molecule drugs target GPCR (NAT. Rev. Drug disc., 2017, 16, 829 – 842). The GPCR superfamily is composed of more than 800 members, among which more than 300 potential drug targets are found. Among them, dopamine receptor is an important drug target of central nervous system, which is related to schizophrenia, drug addiction, Parkinson's disease and other neuropsychiatric diseases. It is a challenging research direction to design small molecule drugs for GPCR of central nervous system, which need to overcome the difficulties of target selectivity, blood-brain barrier permeability and so on. Recently, Cheng Jianjun group of Shanghai University of science and technology reported the design and synthesis of dopamine D3 ligands based on the framework of phenylcyclopropylmethylamine (pcpma) in Journal of medical chemistry.
Pcpma is a new type of small molecular skeleton. The cyclopropane structure in the skeleton endows the small molecule with specific stereostructure, so that the molecule has specific target binding force and biological activity. In previous postdoctoral studies, Cheng Jianjun and his collaborators found that small molecular compounds with high affinity and selectivity for serotonin 5-HT2C receptor can be obtained by optimizing the substituents on the benzene ring (J. Med. Chem., 2015, 58, 1992? 2002). Through systematic optimization of drug chemistry, small molecules with good drug like properties can be obtained. These small molecules have good in vivo activities in animal models of mental diseases such as amphetamine induced high spontaneous activity (J. Med. Chem., 2015, 58, 1992-2002; J. Med. Chem., 2016, 59, 578-591; neuropsychopharmacology, 2017, 42, 2163-2177). Furthermore, some of the compounds showed biased activation for 5-HT2C receptor, with novel mechanism of action (J. Med. Chem., 2016, 59, 9866? 9880; J. Med. Chem., 2018, 61, 9841? 9878). (Figure 1)
Figure 1. 5-HT2C agonist based on pcpma skeleton
Recently, based on pcpma, combining the crystal structure information of dopamine D3 receptor and serotonin 5-HT2C receptor, the research group proposed that pcpma mother nucleus can be derived, and bitopic ligand can be designed and synthesized, which has strong affinity and selectivity for dopamine D3 receptor. Through the design, synthesis and biological activity test of more than 40 compounds, our team found several compounds with strong affinity (KI & lt; 5nm) and high selectivity for dopamine D3 receptor. Through the resolution of cyclopropane enantiomers, it is found that the cyclopropane configuration of pcpma skeleton has a significant effect on the affinity and intrinsic activity of the compounds. The same pair of enantiomers of compound 22e has the same affinity for dopamine D3 receptor, but one is an activator ((1R, 2R) - 22e) and the other is an antagonist ((1s, 2S) - 22e). Through molecular docking experiments, the research team revealed the influence of different cyclopropane configurations on the overall conformation of the compound, and explained the molecular mechanism of different intrinsic activities. At the same time, the team also reported a compound with partial agonist activity ((1R, 2R) - 22q), which has not only the advantages of high affinity and high selectivity, but also good metabolic properties and is suitable for further in vivo activity research (Fig. 2).
Figure 2. Dopamine D3 ligand based on pcpma skeleton
The chemical part of the research was mainly completed by Tan Liang, a postdoctoral of Cheng Jianjun research group. The in vitro pharmacological activity and molecular docking experiments were mainly completed by Xi Ping Huang, Ph.D. of UNC Chapel Hill, and Zhou Qingtong, Ph.D. of ihuman Institute. The research work was supported by the start-up fund of Shanghai University of science and technology and the National Natural Science Foundation.
Original text (scan or long press QR code and go to the original page after identification): design and synthesis of bitopic 2-phylcycleopropylmethyllamine (pcpma) derivations as selective dopamine D3 receiver ligandsliang Tan, Qingtong Zhou, Wenzhong Yan, Jian sun, Alan P. kozikowski, Suwen Zhao, Xi Ping Huang, Jianjun Chengj. Med. Chem., 2020, DOI: 10.1021/acs.jmedchem.9b01835
Brief introduction of researcher Cheng Jianjun
Cheng Jianjun is a researcher of ihuman Institute of Shanghai University of science and technology. He graduated from the school of pharmacy of Shandong University in 2005 with a bachelor's degree in pharmacy. In 2010, he graduated from Shanghai Institute of pharmaceutical research, Chinese Academy of Sciences and obtained a doctor's degree in pharmaceutical chemistry, under the guidance of researcher Yang Yushe. From 2010 to 2013, he worked in Shanghai huilun Life Technology Co., Ltd. as a senior researcher and department manager. From 2013 to 2016, he engaged in postdoctoral research at the University of Illinois Chicago Campus, and then joined ihuman Research Institute of Shanghai University of science and technology in March 2016. As the first or corresponding author, he has published more than 20 papers in J Med Chem, J org Chem, NAT commin and other magazines. In 2017, he was selected as "young Oriental scholar" in Shanghai University.
Cheng Jianjun https://www.x-mol.com/university/factory/21374 website of the research group http://chenglab.ihuman.shanghaitech.edu.cn/
Postdoctoral Recruitment Information
At present, there are two postdoctoral positions vacant in Cheng Jianjun's research group, and the research direction is drug chemistry research targeting new GPCR. The research group provides first-class research platform and financial support, and provides competitive salary treatment. We sincerely invite colleagues to join us. Please send your resume to chengjj@shanghaitech.edu.cn. Looking forward to your joining!
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