Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands

doi:10.1021/acs.jmedchem.9b01835

	Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands
	Tan, Liang2 ; Zhou, Qingtong2 ; Yan, Wenzhong2 ; Sun, Jian2 ; Kozikowski, Alan P.3; Zhao, Suwen2,4 ; Huang, Xi-Ping 1; Cheng, Jianjun2
	2020-05-14
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
卷号	63 期号:9 页码:4579-4602
发表状态	已发表
DOI	10.1021/acs.jmedchem.9b01835
摘要	2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (K-i = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.
收录类别	SCI ; SCIE ; IC
语种	英语
资助项目	National Natural Science Foundation of China[81703361][31971178][21704064] ; National Key R&D Program of China[2018YFA0507000]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000535279800013
出版者	AMER CHEMICAL SOC
WOS关键词	AGONISTS ; 2C ; DISCOVERY ; POTENT ; (2-PHENYLCYCLOPROPYL)METHYLAMINES ; 1,2,4-TRIAZOLYL ; IDENTIFICATION ; OPTIMIZATION ; INHIBITION ; TARGETS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/121128
专题	iHuman研究所_PI研究组_程建军组生命科学与技术学院 iHuman研究所_特聘教授组_Andrej Sali组 iHuman研究所_PI研究组_赵素文组
通讯作者	Huang, Xi-Ping; Cheng, Jianjun
作者单位	1.Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Natl Inst Mental Hlth,Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA 2.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 3.StarWise Therapeut LLC, Chicago, IL 60614 USA 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
第一作者单位	iHuman研究所
通讯作者单位	iHuman研究所
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Tan, Liang,Zhou, Qingtong,Yan, Wenzhong,et al. Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(9):4579-4602.
APA	Tan, Liang.,Zhou, Qingtong.,Yan, Wenzhong.,Sun, Jian.,Kozikowski, Alan P..,...&Cheng, Jianjun.(2020).Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands.JOURNAL OF MEDICINAL CHEMISTRY,63(9),4579-4602.
MLA	Tan, Liang,et al."Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands".JOURNAL OF MEDICINAL CHEMISTRY 63.9(2020):4579-4602.