Development of Novel Therapies or Methamphetamine Abuse

描述（由申请人提供）：甲基苯丙胺（冰毒）滥用继续升级，目前还没有有效的治疗方法。甲基安非他明与囊泡单胺转运蛋白（VMAT2）相互作用，促进多巴胺（DA）释放到细胞质中，并逆转DA转运蛋白（DAT），从而增加细胞外DA浓度，这被认为与其滥用倾向有关。重要的是，目前项目的进展表明，α -洛贝林（LOB）对VMAT2上的[3H]二氢四苯那嗪结合位点具有高亲和力，并能有效抑制[3H]DA摄取到突触囊泡。我们还表明，LOB抑制甲基苯丙胺诱导的DA体外释放和甲基苯丙胺在大鼠体内的自我给药。因此，LOB有潜力成为治疗甲基苯丙胺滥用的新治疗剂，最近已成功完成i期临床试验。然而，LOB已被证明与许多不同的CMS靶点相互作用（即它是一种相对非选择性或“脏”的药物），包括alpha4beta2*， alpha6beta2 *和alpha3beta4*烟碱乙酰胆碱受体。在目前的提案中，我们的目标是开发对VMAT2具有高亲和力和选择性的LOB类似物，我们相信这将比LOB作为治疗甲基苯丙胺滥用的治疗候选物具有更大的益处。我们选择VMAT2作为靶点，因为它是DA突触传递的一个关键调控点，由于LOB对VMAT2的高亲和力，并且由于METH与VMAT2的相互作用，导致细胞外DA增加，这与它的奖励和滥用有关。因此，我们的假设侧重于VMAT2作为治疗冰毒滥用的新治疗靶点。选择性的、高亲和力的VMAT2抑制剂的开发将使我们能够验证VMAT2的选择性抑制会降低甲基苯丙胺奖励的假设。我们已经确定了lobelane作为我们的先导化合物，因为它对VMAT2具有高亲和力和相对选择性，它能够抑制冰毒诱发的DA释放，并且它能够减少冰毒的自我给药。因此，本研究的长期目标是开发新的lobelane类似物作为甲基苯丙胺滥用的治疗方法，开拓一类新的治疗药物的开发，选择性地靶向VMAT2，并有潜力作为甲基苯丙胺滥用的有效治疗方法。

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse continues to escalate and effective treatments are not yet available. METH interacts with the vesicular monoamine transporter (VMAT2), promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter (DAT) to increase extracellular DA concentrations, which is thought to be associated with its abuse liability. Importantly, progress on the current project has shown that alpha-lobeline (LOB) has high affinity for the [3H]dihydrotetrabenazine binding site on VMAT2 and potently inhibits [3H]DA uptake into synaptic vesicles. We have also shown that LOB inhibits METH-evoked DA release in vitro and METH self-administration in rats. Thus, LOB has potential as a new therapeutic agent for the treatment of METH abuse, and has recently successfully completed Phase 1 a clinical trials. However, LOB has been shown to interact with many different CMS targets (i.e. it is a relatively nonselective or "dirty" drug), including alpha4beta2*, alpha6abeta2* and alpha3beta4* nicotinic acetylcholine receptors. In the current proposal, we aim to develop LOB analogs with high affinity and selectivity for VMAT2, which we believe will have increased benefits over LOB as therapeutic candidates for the treatment of METH abuse. We chose VMAT2 as the target as it is a key point of regulation in DA synaptic transmission, due to the high affinity of LOB for VMAT2, and due to METH's interaction with VMAT2, which results in increased extracellular DA that is associated with its reward and abuse. Thus, our hypothesis focuses on VMAT2 as a novel therapeutic target for the treatment of METH abuse. Development of selective, high affinity VMAT2 inhibitors will allow us to test the hypothesis that selective inhibition of VMAT2 decreases METH reward. We have identified lobelane as our lead compound due to its high affinity and relative selectivity for VMAT2, its ability to inhibit METH-evoked DA release, and its ability to decrease METH self-administration. Thus, the long-term goal of this research is to develop novel lobelane analogs as treatments for METH abuse, pioneering the development of a novel class of therapeutic agents that selectively target VMAT2 and have potential as efficacious treatments for METH abuse.