title: Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression.
abstract: We report the synthesis of novel, potentially hypnotic fluorine-substituted phenyl acetate derivatives. We describe the structure-activity relationship that led us to the promising derivative: ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-fluorophenyl) acetate (55). The unique pharmacological features of compound 55 are its relatively high affinity for the GABAA receptor, together with a unique affinity for the NMDA receptor, different to propanidid and AZD3043. In animal models, compound 55 showed stronger hypnotic potency and longer duration of LORR than propanidid and AZD3043, but also maintained a rapid recovery time to walking and behavioral recovery. In particular, compound 55 displayed reflex depression during infusion.
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: Heng
authors.initials: H
authors.lastname: Zhang
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: Yin
authors.initials: Y
authors.lastname: Chen
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: 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: D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005461:Fluorine / Q000737:chemistry*; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012018:Reflex / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D006993:Hypnotics and Sedatives; D010636:Phenols; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D005461:Fluorine; C570634:phenyl acetate
keywords: Fluorine-substituted; GABA(A) receptor; Hypnotic agent; Phenyl acetate derivative