The first reversible radioligand for the hVMAT2 [3H]reserpine binding site

描述（由申请人提供）：滥用甲基苯丙胺（MA）是一个主要的健康问题。大约有1000万美国人至少使用过一次MA。长期使用MA具有深远的健康后果，并具有巨大的社会影响。国家药物滥用研究所对发现解决这一问题的药物表示了相当大的兴趣。然而，目前没有药物可用于治疗MA成瘾。MA是位于单胺神经末梢细胞内储存囊泡上的水疱单胺转运蛋白-2 （VMAT2）的底物。这个第一阶段项目的目标是设计一种有效的、选择性的放射性配体，在与VMAT2的功能活性耦合的结合位点可逆地标记VMAT2。与VMAT2功能活性相关的可逆[3H]配体将加速MA滥用药物的研究。本文提出的独特配体旨在通过抑制VMAT2上的[3H]利血平结合位点来抑制VMAT2的摄取。在我们的实验室中，一种新型芳基哌啶基喹唑啉（APQ）的先导化合物已经被证明在VMAT2上的[3H]利血平结合位点可逆结合。该化合物的优化现在将通过对VMAT2的结合效力和拮抗剂效力的顺序分子修饰来实现，通过VMAT2对血清素和多巴胺摄取的抑制来测量。将进行进一步的分子修饰以优化对竞争结合位点的选择性。将引入拓扑变化来探索VMAT2抑制的三维要求。VMAT2结合位点的生物对映体选择性将通过对映纯化合物的评价来开发。将对化合物进行修饰，以优化电子、立体和亲脂因子对VMAT2的功能和抑制效力。该项目预计将对MA药物治疗的研究以及对MA分子相互作用和靶向VMAT2的潜在药物的理解产生重大影响。

DESCRIPTION (provided by applicant): Abuse of methamphetamine (MA) is a major health problem. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and has a tremendous societal impact. The National Institute on Drug Abuse has expressed considerable interest in the discovery of medications to address this problem. However, currently no medications are available for treatment of MA addiction. MA is a substrate for the Vesicular Monoamine Transporter-2 (VMAT2) located on intracellular storage vesicles in monoaminergic nerve terminals. The goal of this Phase 1 project is to design a potent and selective radioligand that reversibly labels the VMAT2 at a binding site that is coupled to functional activity of the VMAT2. A reversible [3H]ligand linked to functional activity f the VMAT2 will accelerate research toward discovery of medications for MA abuse. The unique ligands proposed here are designed to inhibit VMAT2 uptake by inhibition of the little explored [3H]reserpine binding site on VMAT2. A lead compound in the novel class of arylpiperidinylquinazolines (APQ) has already been demonstrated in our laboratories to bind reversibly at the [3H]reserpine binding site on the VMAT2. Optimization of this compound will now be achieved by sequential molecular modification with respect to binding potency at the VMAT2 and antagonist potency, as measured by inhibition of serotonin and dopamine uptake by the VMAT2. Further molecular modification will be conducted to optimize selectivity against competing binding sites. Topological changes will be introduced to explore the three-dimensional requirements of VMAT2 inhibition. Bioenantioselectivity of the VMAT2 binding site will be exploited by evaluation of enantiopure compounds. Compounds will be modified to optimize electronic, steric and lipophilic factors on functional and inhibitory potency at VMAT2. This project is expected to have a high impact on the search for MA pharmacotherapies as well as on the understanding of the molecular interaction of MA and potential medications that target the VMAT2. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse, for which there are currently no medications available, has far reaching health consequences and a substantial societal impact. The goal of this project is to design radioligands as molecular tools to explore the interaction of methamphetamine with its biological target, the Vesicular Monoamine Transporter. These tools will accelerate the search for medications for methamphetamine addiction.