BRAIN DISTRIBUTION OF POTENT DOPAMINE TRANSPORT INHIBITOR O 1059

单胺多巴胺、血清素和 去甲肾上腺素是大多数 抗抑郁药，哌甲酯（利他林），最常见的 治疗注意力缺陷多动症的处方药 精神紊乱，还有可卡因。 通过阻断单胺 转运蛋白和提高单胺水平，药物触发 生化事件级联，导致治疗获益，或 可卡因、兴奋剂作用和滥用责任的情况。 没有 治疗药物和其他药物的分子结构， 调节单胺转运蛋白已被设计成具有胺 分子结构中的氮。 我们最近报道了一个独特的 一系列不含胺氮的化合物（芳基氧杂阿托品）， 它们的结构（非胺）仍然是多巴胺的有效抑制剂， 传送器 本研究的目的是确定 九胺的大脑分布是否与已知的 多巴胺转运体在恒河猴脑内的分布 （Macaca mulatta）. 最初，进行了参数研究， 建立适当预孵育、孵育和缓冲液洗涤 次 随后，孵育20 mm冠状组织切片 用[3H] O-1059（0.3 nM）测定总结合，可卡因（30 mM） 来测量非特异性结合。 放射自显影分析 [3H] O-1059的分布随后在9个 不同的大脑区域，6个前向后平面。 密集 在纹状体中发现了标记， 在其他脑区观察到的。 分布格局相似 与用选择性单胺配体（[3H] CFT或 [3H] WIN 35，428），表明不存在胺氮 影响多巴胺转运抑制剂的大脑分布。 总的来说，这些数据支持进一步开发非胺， 产生转运抑制剂。

The transporters for the monoamines dopamine, serotonin and norepinephrine are principal targets for the majority of antidepressant drugs, methylphenidate (Ritalin), the most frequently prescribed drug for treatment of Attention Deficit Hyperactivity Disorder, and the addictive drug cocaine. By blocking monoamine transporters and elevating monoamine levels, the drugs trigger a cascade of biochemical events, leading to therapeutic benefit or, in the case of cocaine, stimulant effects and abuse liability. Without exception, the molecular structure of therapeutic and other drugs that modulate monoamine transporters have been designed with an amine nitrogen in the molecular structure. We recently reported a unique series of compounds (aryloxatropanes) that bear no amine nitrogen in their structure (nonamines) yet are potent inhibitors of the dopamine transporter. The objective of the present study was to determine whether the brain distribution of a nonamine corresponds to the known distribution of the dopamine transporter in rhesus monkey brain (Macaca mulatta). Initially, parametric studies were conducted to establish appropriate pre-incubation, incubation, and buffer wash times. Subsequently, 20 mm coronal tissue sections were incubated with [3H]O-1059 (0.3 nM) to measure total binding, and cocaine (30 mM) to measure nonspecific binding. Autoradiographic analysis of the distribution of the [3H]O-1059 was subsequently performed in 9 distinct brain regions, of 6 anterior to posterior planes. Dense labelling was noted in the striatum and considerably lower levels were observed in other brain regions. The distribution pattern was similar to that obtained with the selective monoamine ligand ([3H]CFT or [3H]WIN 35,428), indicating that the absence of an amine nitrogen does affect brain distribution of potent dopamine transport inhibitors. Overall, these data support further development of nonamines, a new generation of transport inhibitors.