Development of Novel Therapies or Methamphetamine Abuse

描述(申请人提供)：甲基苯丙胺(冰毒)滥用继续上升，目前还没有有效的治疗方法。Meth与囊泡单胺转运体(VMAT2)相互作用，促进多巴胺(DA)释放到胞浆中，并逆转DA转运体(DAT)，以增加细胞外DA浓度，这被认为与其滥用倾向有关。重要的是，本项目的进展表明，α-洛贝林(LOB)与VMAT2上的[~3H]二氢四苯并嗪结合部位有很高的亲和力，并有效地抑制[~3H]DA进入突触小泡。我们还发现，LOB在体外可抑制冰毒诱发的DA释放，并能抑制大鼠冰毒自身给药。因此，LOB具有作为治疗冰毒滥用的新治疗剂的潜力，最近成功地完成了第一阶段a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α4beta2*、alpha6abeta2*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，我们相信这种类似物作为治疗冰毒滥用的候选药物将比LOB有更大的益处。我们选择VMAT2作为靶点，是因为它是DA突触传递的关键调节点，因为LOB对VMAT2具有很高的亲和力，而且由于Meth与VMAT2的相互作用，导致与其奖赏和滥用相关的细胞外DA增加。因此，我们的假设集中在VMAT2作为治疗冰毒滥用的新的治疗靶点。开发选择性、高亲和力的VMAT2抑制剂将使我们能够检验选择性抑制VMAT2会减少冰毒奖励的假设。我们确定洛贝兰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，它能抑制甲基诱发的DA释放，以及它能减少冰毒的自我给药。因此，这项研究的长期目标是开发新的洛贝兰类似物作为治疗冰毒滥用的方法，率先开发一类新的治疗药物，选择性地针对VMAT2，并有可能作为治疗冰毒滥用的有效方法。

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.