Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics.
In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors, together with a low affinity for H₁ receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine.
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.
Yin
Y
Chen
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Yu
Y
Lan
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Songlin
S
Wang
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Heng
H
Zhang
Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
Xiangqing
X
Xu
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Xin
X
Liu
Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
Minquan
M
Yu
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Bi-Feng
BF
Liu
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.
Guisen
G
Zhang
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D021241:Spectrometry, Mass, Electrospray Ionization
D014150:Antipsychotic Agents; D003374:Coumarins
Atypical antipsychotics; Coumarin; Dopamine; Serotonin