Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1)

Hai-Jian Fu; Yang Zhao; Yu-Ren Zhou; Bei-Hua Bao; Yun Du; Jian-Xin Li

doi:10.1016/j.ejps.2015.04.021

Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1)

Eur J Pharm Sci. 2015 Aug 30:76:33-47. doi: 10.1016/j.ejps.2015.04.021. Epub 2015 Apr 28.

Authors

Hai-Jian Fu¹, Yang Zhao¹, Yu-Ren Zhou¹, Bei-Hua Bao¹, Yun Du¹, Jian-Xin Li²

Affiliations

¹ State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China.
² State Key Lab of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, PR China. Electronic address: lijxnju@nju.edu.cn.

PMID: 25930119
DOI: 10.1016/j.ejps.2015.04.021

Abstract

Tryptophan hydroxylase 1 (Tph-1) initiates the biosynthesis of peripheral serotonin. As peripheral serotonin suppresses bone formation, inhibitor of Tph-1 provides a useful tool to discover anabolic agents for osteoporosis. In the present study, series of ursolic acid (UA) derivatives were synthesized, and their inhibitory activity on serotonin biosynthesis and cytotoxicity were evaluated. Among the derivatives, 8d with potent inhibitory activity on serotonin was applied for further research. The data revealed that 8d significantly inhibited protein and mRNA expressions of Tph-1, and an SPR study indicated that 8d directly interacted to Tph-1 with a binding affinity of KD=15.09μM. Oral administration of 8d significantly prevented bone loss via suppressing serotonin biosynthesis without estrogenic side-effects in ovariectomized (OVX) rats.

Keywords: Bone formation; Serotonin; Tryptophan hydroxylase 1 (Tph-1); Ursolic acid derivatives.

Publication types

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

MeSH terms

Administration, Oral
Animals
Binding Sites
Bone Density Conservation Agents / administration & dosage
Bone Density Conservation Agents / chemistry
Bone Density Conservation Agents / metabolism
Bone Density Conservation Agents / pharmacology*
Catalytic Domain
Disease Models, Animal
Down-Regulation
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Female
Gene Expression Regulation, Neoplastic
Humans
Molecular Docking Simulation
Osteogenesis / drug effects*
Osteoporosis, Postmenopausal / enzymology
Osteoporosis, Postmenopausal / physiopathology
Osteoporosis, Postmenopausal / prevention & control*
Ovariectomy
Protein Binding
Protein Conformation
RNA, Messenger / metabolism
Rats
Serotonin / biosynthesis*
Serotonin / blood
Structure-Activity Relationship
Triterpenes / administration & dosage
Triterpenes / chemistry
Triterpenes / metabolism
Triterpenes / pharmacology*
Tryptophan Hydroxylase / antagonists & inhibitors*
Tryptophan Hydroxylase / genetics
Tryptophan Hydroxylase / metabolism
Ursolic Acid

Substances

Bone Density Conservation Agents
Enzyme Inhibitors
RNA, Messenger
Triterpenes
Serotonin
Tryptophan Hydroxylase
tph1 protein, rat