Discovery and synthesis of novel luteolin derivatives as DAT agonists.
Luteolin, 5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one, has been proposed and proved to be a novel dopamine transporter (DAT) activator. In order to develop this potential of luteolin, a series of novel luteolin derivatives were designed, synthesized, and evaluated for their DAT agonistic activities, utilizing constructed Chinese hamster ovary (CHO) cell lines stably expressing rat DAT. Biological screening results demonstrated that luteolin derivatives 1d, 1e, and 4c carry great DAT agonistic potency (EC(50)=0.046, 0.869, and 1.375μM, respectively) compared with luteolin 8 (EC(50)=1.45±0.29μM). Luteolin derivative 1d, notably, exhibited a 32-fold-higher DAT agonistic potency than luteolin. These luteolin derivatives represent a novel DAT agonist class, from which lead compounds useful for exploration of additional novel DAT agonists could be drawn.
Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China. jgzhang5500@hotmail.com
Jiange
J
Zhang
Xianbo
X
Liu
Xinsheng
X
Lei
Lei
L
Wang
Lihe
L
Guo
Gang
G
Zhao
Guoqiang
G
Lin
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D050483:Dopamine Plasma Membrane Transport Proteins / Q000819:agonists* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047311:Luteolin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D047309:Flavones; D047311:Luteolin