Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists

Yu Xue; Jingshu Tang; Xiaozhuo Ma; Qing Li; Bingxue Xie; Yuchen Hao; Hongwei Jin; Kewei Wang; Guisen Zhang; Liangren Zhang; Lihe Zhang

doi:10.1016/j.ejmech.2016.03.016

Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists

Eur J Med Chem. 2016 Jun 10:115:94-108. doi: 10.1016/j.ejmech.2016.03.016. Epub 2016 Mar 8.

Authors

Yu Xue¹, Jingshu Tang², Xiaozhuo Ma¹, Qing Li¹, Bingxue Xie¹, Yuchen Hao², Hongwei Jin¹, Kewei Wang³, Guisen Zhang⁴, Liangren Zhang⁵, Lihe Zhang¹

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
² Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
³ Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: wangkw@bjmu.edu.cn.
⁴ Jiangsu Nhwa Pharmaceutical Co. Ltd. 69 Minzhu South Road, Xuzhou, Jiangsu, 221116, PR China.
⁵ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: liangren@bjmu.edu.cn.

PMID: 26994846
DOI: 10.1016/j.ejmech.2016.03.016

Abstract

Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure-activity relationship studies provide insights to develop more potent novel α7 nAChR agonists.

Keywords: Agonists; Indolizine; SAR; Schizophrenia; α7 nAChR.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Humans
Indolizines / chemical synthesis*
Indolizines / chemistry
Indolizines / pharmacology*
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor / agonists*

Substances

Indolizines
alpha7 Nicotinic Acetylcholine Receptor
indolizine