Design, synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor

Ming-Liang Ma; Ming Li; Jiao-Jiao Gou; Tian-Yu Ruan; Hai-Shan Jin; Ling-Hong Zhang; Liang-Chun Wu; Xiao-Yan Li; Ying-He Hu; Ke Wen; Zheng Zhao

doi:10.1016/j.bmc.2014.08.038

Design, synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor

Bioorg Med Chem. 2014 Nov 1;22(21):6117-23. doi: 10.1016/j.bmc.2014.08.038. Epub 2014 Sep 8.

Authors

Affiliations

¹ Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai 200062, China; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China.
³ Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai 200062, China.
⁴ Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China. Electronic address: wenk@sari.ac.cn.
⁵ Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai 200062, China. Electronic address: zzhao@brain.ecnu.edu.cn.

PMID: 25262941
DOI: 10.1016/j.bmc.2014.08.038

Abstract

Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC50 value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure-activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2'-fluoride group in ring B were essential for this class of compounds to be active against NMU2R.

Keywords: Flavonoid derivatives; NMU2R; Structure–activity relationship.

Publication types

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

MeSH terms

Drug Design
Flavonoids / chemical synthesis
Flavonoids / chemistry*
Flavonoids / pharmacology*
Humans
Receptors, Neurotransmitter / agonists*
Receptors, Neurotransmitter / metabolism
Structure-Activity Relationship

Substances

Flavonoids
Receptors, Neurotransmitter
neuromedin U receptor