DEVELOPMENT OF NOVEL THERAPIES FOR METHAMPHETAMINE ABUSE

描述：（申请人摘要） 近年来，甲基苯丙胺（METH）的滥用有所升级， 目前还没有减少其使用的治疗方法。我们的初步结果 证明α-洛贝林（LOB），一种弱碱性亲脂性生物碱，与 高亲和力烟碱受体结合位点（α 4 β 2亚型），并作为 烟碱受体亚型的拮抗剂，可引起多巴胺（DA）释放 （据称是a3 P2亚型）。LOB还抑制多巴胺转运蛋白 (DAT)和囊泡单胺转运蛋白（VMAT 2），但不抑制 单胺氧化酶（MAO）。此外，LOB抑制安非他明（AMPT）诱发的DA 释放和METH自我给药。我们的初步结果表明 VMAT 2可能是METH治疗的一个重要新靶点 虐待考虑到这一点，我们已经开始合成一系列LOB类似物， 目标VMAT 2。本建议书的长期目标是发展我们的主要业务线 类似物，2 R，6S-N-甲基-2，6-E-（顺式-苯乙烯基）哌啶（内消旋-反式二烯， MTD）和其它结构上相关的MTD类似物作为METH的新治疗 虐待MTD是LOB的合成衍生物，其与LOB不同，具有可忽略的 对烟碱受体的亲和力，而且靶向DA转运蛋白。 MTD的结构类似物将在神经化学和行为学方面进行评价。 开发VMAT 2的结构活性关系（SAR）的试验 药效团实验旨在测试两个特定的假设。第一、 用MTD或其结构类似物预处理大鼠将减少 胞浆中的DA池可用于MET诱导的DAT的反向转运， 与VMAT 2相互作用，从而减少METH诱导的DA释放。 突触前末梢第二，用MTD或其类似物预处理大鼠， 减少METE自我管理。类似物与 烟碱受体和DATMll也可以评估，因为LOB作用于这些受体。 网站也是。后一种测定的结果将指引SAR朝向 对VMAT 2的选择性更高。MTD类似物，其有效抑制MET诱导的 DA在体外释放并且不与烟碱受体相互作用， 评估它们减少大鼠中METH自我给药的能力。我们 预测对VMAT 2具有高效力和选择性的MTD类似物将是 治疗甲基苯丙胺滥用的最佳人选这些研究将 开创了一类新型治疗药物的发展， VMAT 2和作为METH滥用的有效治疗的潜力。

DESCRIPTION: (Applicant's Abstract) The abuse of methamphetamine (METH) has escalated in recent years and effective treatments to curtail its use are not yet available. Our preliminary results demonstrate that a-lobeline (LOB), a weakly basic lipophilic alkaloid, binds to the high affinity nicotinic receptor binding site (a4P2 subtype) and acts as an antagonist at the nicotinic receptor subtype which evokes dopamine (DA) release (purportedly, the a3P2 subtype). LOB also inhibits the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2), but does not inhibit monoamine oxidase (MAO). Moreover, LOB inhibits amphetamine (AMPT)-evoked DA release and METH self-administration in rats. Our preliminary results suggest that VMAT2 may be an important new therapeutic target for the treatment of METH abuse. With this in mind, we have begun synthesizing a series of LOB analogs to target VMAT2. The long-term goal of this proposal is to develop our lead LOB analog, 2R,6S-N-methyl-2,6-<E-(cis-phenylethenyl)piperidine (meso-transdiene, MTD), and other structurally related MTD analogs as novel treatments for METH abuse. MTD is a synthetic derivative of LOB, which unlike LOB, has negligible affinity for nicotinic receptors, and moreover, targets DA transporters. Structural analogs of MTD will be evaluated in neurochemical and behavioral assays to develop the structure activity relationships (SARs) for the VMAT2 pharmacophore. Experiments are designed to test two specific hypotheses. First, pretreatment of rats with MTD or its structural analogs will reduce the cytosolic pool of DA available for METH-induced reverse transport of DAT via an interaction with VMAT2, and thereby decrease METH-induced DA release from the presynaptic terminal. Second, pretreatment of rats with MTD or its analogs will diminish METE self-administration. The interaction of the analogs with nicotinic receptors and with DATMll also be evaluated, since LOB acts at these sites as well. Results from the latter assays will direct the SAR towards greater selectivity for VMAT2. MTD analogs which potently inhibit METH-induced DA release in vitro and which do not interact at nicotinic receptors will be assessed for their ability to decrease METH self-administration in rats. We predict that MTD analogs with high potency and selectivity for VMAT2 will be the best candidates for the treatment of METH abuse. Thus, these studies will pioneer the development of a novel class of therapeutic agents which target VMAT2 and have potential as efficacious treatments for METH abuse.