Label-free cell phenotypic study of opioid receptors and discovery of novel mu opioid ligands from natural products

doi:10.1016/j.jep.2021.113872

KIB OpenIR

	Label-free cell phenotypic study of opioid receptors and discovery of novel mu opioid ligands from natural products
	Hou,Tao ; Xu,Fangfang ; Peng,Xingrong ; Zhou,Han ; Zhang,Xiuli ; Qiu,Minghua; Wang,Jixia ; Liu,Yanfang ; Liang,Xinmiao
	2021
发表期刊	JOURNAL OF ETHNOPHARMACOLOGY
ISSN	0378-8741
卷号	270 页码:113872
摘要	Ethnopharmacological relevance: Mu opioid receptor (MOR) is mainly a drug target for analgesia. Opioid-like agonists such as morphine have been clinically used for analgesia but have potential adverse effects. MOR antagonists have been demonstrated to alleviate these side effects. Plants (Carthamus tinctorius L, Cynanchum otophyllum C. K. Schneid., Coffea arabica L., Prinsepia utilis Royle and Lepidium meyenii Walp.) and Ganoderma fungi (Ganoderma hainanense J. D. Zhao, Ganoderma capense (Lloyd) Teng, Ganoderma cochlear (Blume et Nees) Bres., Ganoderma resinaceum Boud and Ganoderma applanatum (Pers.) Pat.) are traditional medicines with beneficial effects on immunoregulation, analgesia and the nervous system, but whether MORs are engaged in their effects remains unknown.Aim of the study: This work aimed to identify MOR ligands among compounds isolated from the above-mentioned 10 species, and to investigate selectivity against four opioid receptor subtypes. By analyzing the structure-activity relationship and off-target effects, we could provide a new direction for the future development of MOR drugs. Materials and methods: Four opioid receptor subtype models, including MOR, delta (DOR), kappa (KOR) and nop (NOR), were established with a label-free phenotypic dynamic mass redistribution assay to systematically profile the pharmacological properties of known ligands. Then, 82 natural compounds derived from the 10 species were screened against MOR to identify new ligands. The selectivity of the new ligands was characterized against the four subtypes, and off-target effects were also investigated on eight G protein-coupled receptors (GPCRs).Results: The pharmacological properties of known ligands on transfected HEK293T-MOR, HEK293-DOR, HEK293-KOR and HEK293-NOR cell lines were characterized. Seven compounds purified from Ganoderma cochlear (Blume et Nees) Bres. and Carthamus tinctorius L were MOR antagonists with micromolar potency. Among them, compound 35 showed the strongest antagonistic activity on MOR with an IC50 value of 10.0 +/- 3.0 mu M. To a certain extent, these seven new antagonists, exhibited antagonistic activity on the other opioid receptor subtypes, and they had almost no effect on other GPCRs, including CB1, CB2, M2 and beta2AR. Additionally, a compound from Lepidium meyenii Walp. displayed MOR agonistic activity.Conclusions: The established screening models opened new avenues for the discovery and evaluation of opioid receptor ligand selectivity. Together,the novel MOR antagonists will enrich the inventory of MOR ligands and benefit related therapics.
关键词	Opioid receptors Dynamic mass redistribution Natural products Antagonist Selectivity IDENTIFICATION ANTAGONISTS SUBSTANCES NALOXEGOL AGONISTS SAFETY MACA
DOI	10.1016/j.jep.2021.113872
WOS记录号	WOS:000618540100004
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/73251
专题	中国科学院昆明植物研究所
作者单位	1.Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China 2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China 3.Soochow Univ, Coll Pharmaceut Sci, Suzhou 215123, Peoples R China 4.Chinese Acad Sci, Jiangxi Chinese Med Sci Ctr DICP, Nanchang 330000, Jiangxi, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Chinese Acad Sci, Kunming Inst Bot, Yunnan Key Lab Nat Med Chem, Kunming 650201, Yunnan, Peoples R China
推荐引用方式 GB/T 7714	Hou,Tao,Xu,Fangfang,Peng,Xingrong,et al. Label-free cell phenotypic study of opioid receptors and discovery of novel mu opioid ligands from natural products[J]. JOURNAL OF ETHNOPHARMACOLOGY,2021,270:113872.
APA	Hou,Tao.,Xu,Fangfang.,Peng,Xingrong.,Zhou,Han.,Zhang,Xiuli.,...&Liang,Xinmiao.(2021).Label-free cell phenotypic study of opioid receptors and discovery of novel mu opioid ligands from natural products.JOURNAL OF ETHNOPHARMACOLOGY,270,113872.
MLA	Hou,Tao,et al."Label-free cell phenotypic study of opioid receptors and discovery of novel mu opioid ligands from natural products".JOURNAL OF ETHNOPHARMACOLOGY 270(2021):113872.