Department of Pharmacology and Physiology, Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
J Nat Prod. 2013 Oct 25;76(10):1889-95. doi: 10.1021/np400452n. Epub 2013 Oct 10.
The neurotransmitter transporters of the SLC6 family play critical roles in the regulation of neurotransmission and are the primary targets of therapeutic agents used to treat clinical disorders involving compromised neurotransmitter signaling. The dopamine and norepinephrine transporters have been implicated in clinical disorders such as attention deficit hyperactivity disorder (ADHD) and substance abuse. The GABA transporters (GATs) serve as a target for anxiolytic, antidepressant, and antiepileptic therapies. In this work, the interaction with neurotransmitter transporters was characterized for a derivative of the lignan (-)-cubebin (1), namely, (-)-hinokinin (2). Using in vitro pharmacological assays, 2 selectively inhibited the human dopamine and norepinephrine transporters, in a noncompetitive manner possibly mediated by binding to a novel site within the transporters, and displayed low affinity for the serotonin transporter. Compound 2 also specifically inhibited the GAT-1 GABA transporter subtype. Compound 2 is not a substrate of the carriers as it had no effect on the efflux of either of the neurotransmitters investigated. This compound is inactive toward glutamate and glycine transporters. These results suggest that 2 may serve as a tool to develop new therapeutic drugs for ADHD and anxiety that target the DAT, NET, and GAT-1 transporters.
SLC6 家族的神经递质转运体在神经递质传递的调节中起着关键作用，是治疗涉及神经递质信号转导受损的临床疾病的治疗药物的主要靶点。多巴胺和去甲肾上腺素转运体与注意缺陷多动障碍（ADHD）和物质滥用等临床疾病有关。GABA 转运体（GATs）是抗焦虑药、抗抑郁药和抗癫痫药的作用靶点。在这项工作中，对木脂素（-）-麻椒素（1）的衍生物（-）- hinokinin（2）与神经递质转运体的相互作用进行了表征。使用体外药理学测定法，2 以非竞争性方式选择性抑制人多巴胺和去甲肾上腺素转运体，可能通过与转运体内部的新结合位点结合介导，并且对 5-羟色胺转运体具有低亲和力。化合物 2 还特异性抑制 GAT-1 GABA 转运体亚型。化合物 2 不是载体的底物，因为它对所研究的任何一种神经递质的外排都没有影响。该化合物对谷氨酸和甘氨酸转运体没有活性。这些结果表明，2 可能成为开发针对 DAT、NET 和 GAT-1 转运体的 ADHD 和焦虑新治疗药物的工具。
