Carbazole and tetrahydro-carboline derivatives as dopamine D_(3) receptor antagonists with the multiple antipsychotic-like properties  

作　　者：Zhongtang Li Fan Fang Yiyan Li Xuehui Lv Ruqiu Zheng Peili Jiao Yuxi Wang Guiwang Zhu Zefang Jin Xiangqing Xu Yinli Qiu Guisen Zhang Zhongjun Li Zhenming Liu Liangren Zhang 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [2]Jiangsu Nhwa Pharmaceutical Co.,Ltd.,Xuzhou 221116,China [3]Jiangsu Key Laboratory of Marine Biological Resources and Environment,Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening,School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第11期4553-4577,共25页药学学报（英文版）

基　　金：supported by The National Key R&D Program (2022YFC2303700,China);the Ningxia Hui Autonomous Region Key Research and Development Project (2022BEG02042,China);the National Natural Science Foundation of China (82030108,81803351);Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University (KF-202304,China);the China Postdoctoral Science Foundation (2018M641122,China);the National Major Scientific and Technological Special Project for Significant New Drugs Development (2018ZX09711002-013-004,2018ZX09735-001,China)。

摘　　要：Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and tetrahydro-carboline derivatives were reported as D_(3)R selective ligands.Through a structure-based virtual screen,ZLG-25(D_(3)R K_i=685 nmol/L;D_2R K_i>10,000 nmol/L)was identified as a novel D_(3)R selective bitopic ligand with a carbazole scaffold.Scaffolds hopping led to the discovery of novel D_(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core.Further functional studies showed that most derivatives acted as h D_(3)R-selective antagonists.Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity.Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction.Furthermore,36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests,and alleviated the MK-801-induced disruption of novel object recognition in mice.Additionally,preliminary studies confirmed the favorable PK/PD profiles,no weight gain and limited serum prolactin levels in mice.These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

关 键 词：Dopamine D_(3)receptor Carbazole derivatives Tetrahydro-carboline Bitopic ligand ANTIPSYCHOTIC 

分 类 号：O62[理学—有机化学]