Zhao Gang, Zang Shao-Yun, Zheng Xiang-Wei, Zhang Xiao-Hua, Guo Li-He
Cell Star Bio-Technologies Co., Limited, 898 Halei Road, Shanghai 201203, People's Republic of China.
Biochem Pharmacol. 2008 May 1;75(9):1835-47. doi: 10.1016/j.bcp.2008.01.014. Epub 2008 Feb 7.
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.
单胺转运体在控制单胺水平和调节单胺再摄取方面发挥着关键作用。本研究的目的是从草药来源中鉴定单胺转运体抑制剂。我们发现从补骨脂中分离出的补骨脂酚类似物对单胺转运体摄取有不同程度的抑制作用。补骨脂酚类似物Δ3,2-羟基补骨脂酚是最有效且最具效力的再摄取阻滞剂，因此被选为候选靶点。Δ3,2-羟基补骨脂酚对单胺转运体的抑制作用对多巴胺转运体（DAT）（IC50 = 0.58±0.1微摩尔）和去甲肾上腺素转运体（NET）（IC50 = 0.69±0.12微摩尔）比对5-羟色胺转运体（SERT）（IC50 = 312.02±56.69微摩尔）更具选择性。Δ3,2-羟基补骨脂酚比安非他酮表现出更强的效力（DAT和NET的pEC50），并且对DAT和/或NET的效能（E(max)）与安非他酮和GBR12,935相似。在药代动力学方面，Δ3,2-羟基补骨脂酚以部分可逆的方式竞争性抑制DAT和NET，并占据可卡因结合位点。此外，Δ3,2-羟基补骨脂酚在表达DAT的细胞中对抗1-甲基-4-苯基吡啶鎓诱导的毒性，其效力与GBR12,935相似。体内研究表明，Δ3,2-羟基补骨脂酚增加了正常小鼠的活动，并改善了利血平化小鼠活动减少的情况。在条件性位置偏爱试验中，正常小鼠的偏爱分数不受Δ3,2-羟基补骨脂酚处理的影响。补骨脂酚类似物，尤其是Δ3,2-羟基补骨脂酚，是参与调节多巴胺能和去甲肾上腺素能神经传递的单胺转运体抑制剂，可能代表了帕金森病、抑郁症和可卡因成瘾等疾病的潜在药物治疗方法。
