Bakuchiol analogs inhibit monoamine transporters and regulate monoaminergic functions.
Monoamine transporters play key roles in controlling monoamine levels and modulating monoamine reuptake. The objective of the present study was to identify monoamine transporter inhibitors from herbal sources. We discovered that bakuchiol analogs isolated from Fructus Psoraleae inhibited monoamine transporter uptake to differing degrees. The bakuchiol analog, Delta3,2-hydroxybakuchiol was the most potent and efficacious reuptake blocker and was thus selected as the candidate target. Monoamine transporter inhibition by Delta3,2-hydroxybakuchiol was more selective for the dopamine transporter (DAT) (IC50=0.58+/-0.1 microM) and norepinephrine transporter (NET) (IC50=0.69+/-0.12 microM) than for the serotonin transporter (SERT) (IC50=312.02+/-56.69 microM). Delta3,2-Hydroxybakuchiol exhibited greater potency (pEC50 for DAT and NET) than bupropion and exhibited similar efficacy (E(max) for DAT and/or NET) to bupropion and GBR12,935. Pharmacokinetically, Delta3,2-hydroxybakuchiol competitively inhibited DAT and NET with partial reversibility and occupied cocaine binding sites. Moreover, Delta3,2-hydroxybakuchiol counteracted 1-methyl-4-phenylpyridinium-induced toxicity in cells expressing DAT with similar efficacy to GBR12,935. In vivo studies showed that Delta3,2-hydroxybakuchiol increased the activity of intact mice and improved the decreased activity of reserpinized mice. In the conditioned place preference test, preference scores in intact mice were unaffected by Delta3,2-hydroxybakuchiol treatment. Bakuchiol analogs, especially Delta3,2-hydroxybakuchiol, are monoamine transporter inhibitors involved in regulating dopaminergic and noradrenergic neurotransmission and may have represented potential pharmacotherapies for disorders such as Parkinson's disease, depression, and cocaine addiction.
Zhao
Gang
G
Cell Star Bio-Technologies Co., Limited, 898 Halei Road, Shanghai 201203, People's Republic of China.
Zang
Shao-Yun
SY
Zheng
Xiang-Wei
XW
Zhang
Xiao-Hua
XH
Guo
Li-He
LH
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D003214:Conditioning, Classical / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D005638:Fruit / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D050479:Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010636:Phenols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D029907:Psoralea / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D015306:Biogenic Monoamines; D050479:Neurotransmitter Transport Proteins; D010636:Phenols; D010936:Plant Extracts; C012765:bakuchiol