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Eur J Med Chem. 2016 Nov 29;124:713-728. doi: 10.1016/j.ejmech.2016.09.008. Epub 2016 Sep 4.

Synthesis and biological evaluation of new 6-hydroxypyridazinone benzisoxazoles: Potential multi-receptor-targeting atypical antipsychotics.

Author information

1
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
2
Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
3
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.

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 α1 receptors. 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.

KEYWORDS:

6-Hydroxypyridazinone; Atypical antipsychotics; Multi-receptor-target

PMID:
27639363
DOI:
10.1016/j.ejmech.2016.09.008
[Indexed for MEDLINE]

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