title: Discovery of new muscarinic acetylcholine receptor antagonists from Scopolia tangutica.
abstract: Scopolia tangutica (S. tangutica) is a traditional Chinese medicinal plant used for antispasmodics, anesthesia, analgesia and sedation. Its pharmacological activities are mostly associated with the antagonistic activity at muscarinic acetylcholine receptors (mAchRs) of several known alkaloids such as atropine and scopolamine. With our recent identification of four hydroxycinnamic acid amides from S. tangutica, we hypothesized that this plant may contain previously unidentified alkaloids that may also contribute to its in vivo effect. Herein, we used a bioassay-guided multi-dimension separation strategy to discover novel mAchR antagonists from S. tangutica. The core of this approach is to use label-free cell phenotypic assay to first identify active fractions, and then to guide purification of active ligands. Besides four tropanes and six cinnamic acid amides that have been previously isolated from S. tangutica, we recently identified two new tropanes, one new cinnamic acid amide, and nine other compounds. Six tropane compounds purified from S. tangutica for the first time were confirmed to be competitive antagonists of muscarinic receptor 3 (M3), including the two new ones 8 and 12 with IC50values of 1.97 μM and 4.47 μM, respectively. Furthermore, the cinnamic acid amide 17 displayed 15-fold selectivity for M1 over M3 receptors. These findings will be useful in designing lead compounds for mAchRs and elucidating mechanisms of action of S. tangutica.
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Du
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Jixia
authors.initials: J
authors.lastname: Wang
authors.affiliation: University of Chinese Academy of Sciences, Beijing, China.|Key Lab of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Jian
authors.initials: J
authors.lastname: He
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Lab of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Mei
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226019, China.
authors.forename: Xinmiao
authors.initials: X
authors.lastname: Liang
mesh_terms: D000072283:A549 Cells; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D019073:HT29 Cells; D006801:Humans; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D010641:Phenotype; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D032603:Scopolia / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D000577:Amides; D018680:Cholinergic Antagonists; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3