title: Synthesis and biological evaluation of new 6-hydroxypyridazinone benzisoxazoles: Potential multi-receptor-targeting atypical antipsychotics.
abstract: In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D2, Ki= 0.5 ± 0.07 nM; 5-HT1A, Ki= 5.9 ± 0.8 nM; 5-HT2A, Ki= 0.3 ± 0.01 nM; 5-HT6, Ki= 0.5 ± 0.04 nM) and combined with low affinities for the H1, 5-HT2C, and adrenergic α1receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia.
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: Xudong
authors.initials: X
authors.lastname: Cao
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: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Zhang
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: Minquan
authors.initials: M
authors.lastname: Yu
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: 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: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016503:Drug Delivery Systems / Q000639:trends; D015195:Drug Design; D051379:Mice; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D009593:Nitroimidazoles; D011724:Pyridazines; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A; C009999:benzonidazole
keywords: 6-Hydroxypyridazinone; Atypical antipsychotics; Multi-receptor-target