Bakuchiol analogs inhibit monoamine transporters and regulate monoaminergic functions

• Published in: Biochemical pharmacology 2008-05, Vol.75 (9), p.1835-1847
• Main Authors: Zhao, Gang, Zang, Shao-Yun, Zheng, Xiang-Wei, Zhang, Xiao-Hua, Guo, Li-He
• Format: Article
• Language: English
• Subjects: Animals; Bakuchiol analogs; Biogenic Monoamines - metabolism; Biological and medical sciences; Cell Survival - drug effects; CHO Cells; Conditioning, Classical - drug effects; Cricetinae; Cricetulus; Dopamine transporter; Fruit - chemistry; Humans; Male; Medical sciences; Mice; Mice, Inbred C57BL; Monoamine transporter; Motor Activity - drug effects; Neurotransmitter Transport Proteins - antagonists & inhibitors; Neurotransmitter Transport Proteins - genetics; Norepinephrine transporter; Pharmacology. Drug treatments; Phenols - chemistry; Phenols - isolation & purification; Phenols - pharmacology; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Psoralea - chemistry; Rats; Rats, Sprague-Dawley; Reuptake inhibitor; Synaptosomes - drug effects; Synaptosomes - metabolism; Transfection
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2008.01.014

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, Δ 3,2-hydroxybakuchiol was the most potent and efficacious reuptake blocker and was thus selected as the candidate target. Monoamine transporter inhibition by Δ 3,2-hydroxybakuchiol was more selective for the dopamine transporter (DAT) (IC 50 = 0.58 ± 0.1 μM) and norepinephrine transporter (NET) (IC 50 = 0.69 ± 0.12 μM) than for the serotonin transporter (SERT) (IC 50 = 312.02 ± 56.69 μM). Δ 3,2-Hydroxybakuchiol exhibited greater potency (pEC 50 for DAT and NET) than bupropion and exhibited similar efficacy ( E max for DAT and/or NET) to bupropion and GBR12,935. Pharmacokinetically, Δ 3,2-hydroxybakuchiol competitively inhibited DAT and NET with partial reversibility and occupied cocaine binding sites. Moreover, Δ 3,2-hydroxybakuchiol counteracted 1-methyl-4-phenylpyridinium-induced toxicity in cells expressing DAT with similar efficacy to GBR12,935. In vivo studies showed that Δ 3,2-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 Δ 3,2-hydroxybakuchiol treatment. Bakuchiol analogs, especially Δ 3,2-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.