Synthesis and evaluation of histamine H3 receptor ligand based on lactam scaffold as agents for treating neuropathic pain

Fei Dou; Xudong Cao; Peng Jing; Chunyan Wu; Yuxin Zhang; Yin Chen; Guisen Zhang

doi:10.1016/j.bmcl.2019.04.015

Synthesis and evaluation of histamine H₃ receptor ligand based on lactam scaffold as agents for treating neuropathic pain

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1492-1496. doi: 10.1016/j.bmcl.2019.04.015. Epub 2019 Apr 8.

Authors

Fei Dou¹, Xudong Cao², Peng Jing³, Chunyan Wu³, Yuxin Zhang⁴, Yin Chen⁵, Guisen Zhang⁶

Affiliations

¹ Jiangsu Marine Resources Development Research Institute, HuaiHai Institute of Technology, Lianyungang 222005, China; Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
² Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
³ Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
⁴ College of Life Science, Nanjing Agricultural University, Nanjin 210095, China.
⁵ Jiangsu Marine Resources Development Research Institute, HuaiHai Institute of Technology, Lianyungang 222005, China; Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou, Jiangsu 221116, China. Electronic address: chenyin@hhit.edu.cn.
⁶ Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: gszhang@hust.edu.cn.

PMID: 30981577
DOI: 10.1016/j.bmcl.2019.04.015

Abstract

The synthesis and H₃ receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H₃ and H₁ receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 11 could be a potent candidate for pain treatment.

Keywords: Anti-nociceptive; H(3) receptors; Synthesis.

Publication types

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

MeSH terms

Humans
Lactams / metabolism*
Ligands
Molecular Structure
Neuralgia / drug therapy*
Receptors, Histamine H3 / metabolism*

Substances

Lactams
Ligands
Receptors, Histamine H3