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Bioorg Med Chem Lett. 2016 Jul 1;26(13):3141-3147. doi: 10.1016/j.bmcl.2016.04.087. Epub 2016 Apr 30.

Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics.

Author information

1
CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
2
Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
3
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.
4
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.

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.

KEYWORDS:

5-HT(1A); 5-HT(2A); Catalepsy; D(2); PCP-induced hyperactivity

PMID:
27173799
DOI:
10.1016/j.bmcl.2016.04.087
[Indexed for MEDLINE]

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