title: Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics.
abstract: In the present study, a series of benzamides, endowed with potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-N-methylbenzamide (21) and its fluoro-substituted analogue (22) held the best pharmacological binding profiles. They not only presented potent activities for D2, 5-HT1A, and 5-HT2A receptors, but were also endowed with low activities for 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity of inducing weight gain and QT prolongation. In animal models, compounds 21 and 22 reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. It thus provides potential candidates for further preclinical studies.
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Feipu
authors.initials: F
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Jiang
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
authors.forename: Minghao
authors.initials: M
authors.lastname: Bi
authors.affiliation: Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Chen
authors.affiliation: Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Yin
authors.affiliation: Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Xie
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Hu
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Mingshuo
authors.initials: M
authors.lastname: Xu
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Guo
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: wangzhen@simm.ac.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: heyang@simm.ac.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.affiliation: CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D010622:Phencyclidine; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D010622:Phencyclidine
keywords: 5-HT(1A); 5-HT(2A); Catalepsy; D(2); PCP-induced hyperactivity