|Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression|
|Yang, Tong-Hua; Ma, Yun-Bao; Geng, Chang-An; Yan, De-Xiu; Huang, Xiao-Yan; Li, Tian-Ze; Zhang, Xue-Mei; Chen, Ji-Jun
|发表期刊||EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
|摘要||Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 mu M agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs. (C) 2018 Elsevier Masson SAS. All rights reserved.|
|资助信息||National Natural Science Foundation of China; Program of Yunling Scholarship; CAS Hundred Talents Program; Youth Innovation Promotion Association, CAS; Applied Basic Research Programs of Yunnan Province|
|资助项目||National Natural Science Foundation of China
; National Natural Science Foundation of China
; Program of Yunling Scholarship
; CAS Hundred Talents Program
; Youth Innovation Promotion Association, CAS
; Applied Basic Research Programs of Yunnan Province[2017FB137]
|作者单位||Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Yunnan Key Lab Nat Med Chem, Kunming 650201, Yunnan, Peoples R China|
Yang, Tong-Hua,Ma, Yun-Bao,Geng, Chang-An,et al. Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,156:381-393.
Yang, Tong-Hua.,Ma, Yun-Bao.,Geng, Chang-An.,Yan, De-Xiu.,Huang, Xiao-Yan.,...&Chen, Ji-Jun.(2018).Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,156,381-393.
Yang, Tong-Hua,et al."Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 156(2018):381-393.