Development of Novel Therapies or Methamphetamine Abuse

描述（由申请人提供）：本竞争性修订申请是对通知编号：NOT-OD-09-058和通知标题：NIH宣布恢复法案资金可用性的回应，并被提议作为我们当前R 01资助DA 13519的竞争性补充，标题为“甲基苯丙胺滥用新型疗法的开发”（FOA为PA 07070）。目前，甲基安非他明滥用没有治疗方法。该项目的总体目标是为治疗甲基安非他明滥用提供临床候选药物。我们请求2年的支持，以扩大我们特定目标的范围，并加速用于人类受试者测试的临床候选药物的临床前开发。最近，我们发现了一种新的结构（GZ-793 A），在最初的资助申请中没有描述。在通过集中于与囊泡单胺转运蛋白-2（VMAT 2）有效和选择性相互作用的化合物的神经化学测定筛选的所有化合物中，GZ-793 A在降低对静脉内甲基苯丙胺的反应方面表现出最大的效力和特异性。GZ-793 A可完全阻断大鼠的甲基苯丙胺自我给药（SA），而对蔗糖的反应无任何改变，即，它能特异性地减少甲基苯丙胺SA GZ-793 A的物理化学性质相对于资助项目中最初提出的大多数化合物提供了增强的溶解性和可药用性。在本竞争性修订申请中，我们建议优化GZ-793 A的化学结构，以确保这一有前途的新类别的几种化合物可用作先导化合物GZ-793 A的备份。我们将在神经化学试验中评估本竞争性修订申请中描述的这一系列新型优化化合物，以获得有效和选择性的VMAT 2抑制剂作为额外的结构优化的先导化合物。在急性和重复给药后，将在甲基苯丙胺SA试验中评价这些先导化合物。我们还建议在全面的药代动力学评价中评估我们目前的先导化合物GZ-793 A和本研究中出现的3-4种额外的先导化合物，以评估它们的可药性，以及它们在口服给药后减少甲基苯丙胺SA的能力。我们的目标是在竞争性修订申请的第二年年底之前确定一种可药用、口服生物可利用的临床候选药物，以进行全面的毒理学评价，为向FDA提交的研究性新药申请（IND）做准备。该项目将通过增聘4名博士后研究员和2名技术人员，并通过采购更多的研究设备来刺激经济。评价一系列补充性甲基苯丙胺阻滞剂的这一项目将在2年内完成。与此同时，母项目赠款将按原提议继续使用，因此预计母项目剩余部分的预算不会发生变化。新的资金将加快我们的生产力，使我们能够追求这一新的，但相关的，调查路线的结果，获得临床候选人的治疗甲基苯丙胺滥用。 公共卫生相关性：本竞争性修订申请是对通知编号：NOT-OD-09-058和通知标题：NIH宣布恢复法案资金的可用性的回应，并被提议作为我们当前R 01资助DA 13519的竞争性补充，标题为“甲基苯丙胺滥用新型疗法的开发”（FOA为PA 07070）。目前，甲基安非他明滥用没有治疗方法。该项目的总体目标是为治疗甲基安非他明滥用提供临床候选药物。最近，我们发现了一种新的结构（GZ-793 A），它有效地和选择性地与囊泡单胺转运蛋白-2相互作用，并在动物模型中表现出降低静脉注射甲基苯丙胺反应的效力和特异性。我们建议优化GZ-793 A的化学结构，提供额外的可口服生物利用度临床候选药物，并对其进行全面的毒理学评价，以准备向FDA提交的研究性新药申请（IND）。

DESCRIPTION (provided by applicant): This Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as a competitive supplement to our current R01 grant DA 13519, titled "Development of Novel Therapies for Methamphetamine Abuse" (FOA is PA07070). Currently, there is no treatment available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. We request 2 years of support to expand the scope of our specific aims and accelerate the preclinical development of a clinical candidate for testing in human subjects. Recently, we have identified a novel structure (GZ-793A) that was not described in the original funded application. Among all the compounds screened through the neurochemical assays focusing on compounds which potently and selectively interact with the vesicular monoamine transporter-2 (VMAT2), GZ-793A has exhibited the greatest potency and specificity in decreasing responding for intravenous methamphetamine. GZ-793A produced a complete blockade of methamphetamine self-administration (SA) in rats, without any alteration in responding for sucrose, i.e., it specifically decreases methamphetamine SA. The physicochemical properties of GZ-793A provides enhanced solubility and drugability relative to the majority of compounds initially proposed in the funded project. In this Competitive Revision Application, we propose to optimize the chemical structure of GZ- 793A to ensure that several compounds of this promising new class are available as backups for the lead compound GZ-793A. We will evaluate this novel series of optimized compounds described in this Competitive Revision Application in the neurochemical assays to obtain a potent and selective VMAT2 inhibitor as additional structurally optimized lead compounds. These lead compounds will be evaluated in the methamphetamine SA assay following acute and repeated administration. We also propose to evaluate our current lead compound GZ-793A and the 3-4 additional lead compounds emerging from this research in comprehensive pharmacokinetic evaluations to assess their drugability, as well as their ability to decrease methamphetamine SA following oral administration. Our goal by the end of the 2nd year of the Competitive Revision Application is to have identified a drugable, orally bioavailable, clinical candidate to move to comprehensive toxicological evaluation for preparation of an Investigational New Drug application (IND) to the FDA. This project will stimulate the economy through the hiring of 4 additional postdoctoral fellows and 2 additional technical staff, and through the procurement of additional equipment to conduct the studies. This project evaluating a complementary series of methamphetamine blockers will be completed within 2 years. Concurrently, the parent grant will continue as originally proposed, such that no budgetary changes for the remainder of the parent project are anticipated. The new funds will accelerate our productivity and allow us to pursue this new, but related, line of investigation toward the outcome of obtaining a clinical candidate for the treatment of methamphetamine abuse. PUBLIC HEALTH RELEVANCE: This Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as a competitive supplement to our current R01 grant DA 13519, titled "Development of Novel Therapies for Methamphetamine Abuse" (FOA is PA07070). Currently, there is no treatment available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently, we identified a novel structure (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model. We propose to optimize the chemical structure of GZ- 793A, provide additional leads that are drugable orally-bioavailable clinical candidates and bring them to comprehensive toxicological evaluation for preparation of an Investigational New Drug application (IND) to the FDA.