A novel compound N(1),N(5)-(Z)-N(10)-(E)-tri-p-coumaroylspermidine isolated from Carthamus tinctorius L. and acting by serotonin transporter inhibition.
Safflower, the dry flower of Carthamus tinctorius L., has long been applied for empirically treating cerebral ischemia and depression in traditional Chinese medicine. Pathogenesis of major depression involves monoaminergic transmission. The present study assessed whether safflower or its isolate would be effective in functionally regulating monoamine transporter using in vitro screening cell lines. We discovered that safflower insoluble fraction significantly inhibited serotonin uptake in Chinese hamster ovary cells stably expressing serotonin transporter (i.e. S6 cells). This fraction went through an activity-guided isolation and an active ingredient was obtained, which was subsequently elucidated as a novel coumaroylspermidine analog N(1),N(5)-(Z)-N(10)-(E)-tri-p-coumaroylspermidine using NMR techniques. Pharmacologically, this compound potently and selectively inhibited serotonin uptake in S6 cells or in synaptosomes, with IC(50) of 0.74+/-0.15 microM for S6 cells or 1.07+/-0.23 microM for synaptosomes and with a reversible competitive property for the 5HT-uptake inhibition. The potency of it for 5HT uptake was weaker than that of fluoxetine whereas efficacy generally similar for both. Animals treated with this testing compound showed a significant decrease in synaptosomal 5HT uptake capacity. Thus, N(1),N(5)-(Z)-N(10)-(E)-tri-p-coumaroylspermidine is a novel serotonin transporter inhibitor, which could improve neuropsychological disorders through regulating serotoninergic transmission.
Zhao
Gang
G
Cell Star Bio-Technologies Co., Limited, 898 Halei Road, Shanghai 201203, People's Republic of China.
Gai
Yue
Y
Chu
Wen-Jing
WJ
Qin
Guo-Wei
GW
Guo
Li-He
LH
D000818:Animals; D016466:CHO Cells; D031187:Carthamus tinctorius / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D003373:Coumaric Acids / Q000302:isolation & purification* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification* / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013095:Spermidine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D003373:Coumaric Acids; D004365:Drugs, Chinese Herbal; D005473:Fluoxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013095:Spermidine; C440200:N1,N5,N10-tris(4-coumaroyl)spermidine