title: Synthesis and biological evaluation of a novel sigma-1 receptor antagonist based on 3,4-dihydro-2(1H)-quinolinone scaffold as a potential analgesic.
abstract: The synthesis and sigma-1 receptor (σ1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure-activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1-(4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (Kiσ1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment.
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Bi-Feng
authors.initials: BF
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China. Electronic address: gszhang@mail.hust.edu.cn.
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000008:administration & dosage; D006168:Guinea Pigs; D006873:Hydroquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D059226:Nociceptive Pain / Q000139:chemically induced / Q000517:prevention & control*; D010147:Pain Measurement; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D005557:Formaldehyde; D006873:Hydroquinones; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000594238:3,4-dihydro-2(1H)-quinolinone
keywords: 3,4-Dihydro-2(1H)-quinolinone; Analgesic; Antagonist; Sigma-1 receptor