Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs

Mingshuo Xu; Yu Wang; Feipu Yang; Chunhui Wu; Zhen Wang; Bin Ye; Xiangrui Jiang; Qingjie Zhao; Jianfeng Li; Yongjian Liu; Junchi Zhang; Guanghui Tian; Yang He; Jingshan Shen; Hualiang Jiang

doi:10.1016/j.bmcl.2018.01.038

Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs

Bioorg Med Chem Lett. 2018 Feb 15;28(4):606-611. doi: 10.1016/j.bmcl.2018.01.038. Epub 2018 Jan 31.

Authors

Mingshuo Xu¹, Yu Wang², Feipu Yang², Chunhui Wu³, Zhen Wang², Bin Ye³, Xiangrui Jiang², Qingjie Zhao², Jianfeng Li², Yongjian Liu³, Junchi Zhang², Guanghui Tian³, Yang He⁴, Jingshan Shen⁵, Hualiang Jiang²

Affiliations

¹ CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
² CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
³ Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Shanghai 201209, China.
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.
⁵ CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: shenjingshan@simm.ac.cn.

PMID: 29395980
DOI: 10.1016/j.bmcl.2018.01.038

Abstract

In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D₂, serotonin 5-HT_1A and 5-HT_2A receptors, but also exhibited low potency for α_1A, H₁ and 5-HT_2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold.

Keywords: 5-HT(1A) receptor; Antipsychotic; Multi-receptor; PCP-induced hyperlocomotion; Pyridinecarboxamide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry
Antipsychotic Agents / metabolism
Antipsychotic Agents / pharmacology*
Aripiprazole / pharmacology
Dopamine D2 Receptor Antagonists / chemical synthesis
Dopamine D2 Receptor Antagonists / chemistry
Dopamine D2 Receptor Antagonists / metabolism
Dopamine D2 Receptor Antagonists / pharmacology
Humans
Male
Mice, Inbred ICR
Microsomes, Liver / metabolism
Molecular Structure
Picolinic Acids / chemical synthesis
Picolinic Acids / chemistry
Picolinic Acids / metabolism
Picolinic Acids / pharmacology*
Risperidone / pharmacology
Serotonin 5-HT1 Receptor Antagonists / chemical synthesis
Serotonin 5-HT1 Receptor Antagonists / chemistry
Serotonin 5-HT1 Receptor Antagonists / metabolism
Serotonin 5-HT1 Receptor Antagonists / pharmacology
Serotonin 5-HT2 Receptor Antagonists / chemical synthesis
Serotonin 5-HT2 Receptor Antagonists / chemistry
Serotonin 5-HT2 Receptor Antagonists / metabolism
Serotonin 5-HT2 Receptor Antagonists / pharmacology
Structure-Activity Relationship

Substances

Antipsychotic Agents
Dopamine D2 Receptor Antagonists
Picolinic Acids
Serotonin 5-HT1 Receptor Antagonists
Serotonin 5-HT2 Receptor Antagonists
Aripiprazole
Risperidone