Development of Novel Therapies or Methamphetamine Abuse

描述（由申请人提供）：本竞争性修订申请是为了响应通知编号：no - od -09-058和通知标题：NIH宣布恢复法案资金的可用性，并提议作为我们当前R01拨款DA 13519的竞争性补充，标题为“开发甲基苯丙胺滥用的新疗法”（FOA为PA07070）。目前，没有针对甲基苯丙胺滥用的治疗方法。该项目的总目标是提供一种治疗甲基苯丙胺滥用的临床候选药物。我们请求2年的支持，以扩大我们特定目标的范围，并加速临床候选药物的临床前开发，以进行人体试验。最近，我们发现了一种新的结构（GZ-793A），在最初的资助申请中没有描述。在所有通过神经化学分析筛选的化合物中，重点关注与水疱单胺转运蛋白-2 （VMAT2）有效和选择性相互作用的化合物，GZ-793A在降低静脉注射甲基苯丙胺反应方面表现出最大的效力和特异性。GZ-793A对大鼠甲基苯丙胺自我给药（methamphetamine self-给药，SA）产生完全阻断作用，对蔗糖的反应没有任何改变，即特异性降低甲基苯丙胺SA。相对于该项目最初提出的大多数化合物，GZ-793A的物理化学性质提供了更高的溶解度和药物性。在本次竞争性修订申请中，我们建议对GZ-793A的化学结构进行优化，以确保这类有前途的新化合物可以作为先导化合物GZ-793A的后备化合物。我们将评估本竞争性修订中描述的新系列优化化合物在神经化学分析中的应用，以获得有效和选择性的VMAT2抑制剂作为额外的结构优化先导化合物。这些先导化合物将在急性和重复给药后的甲基苯丙胺SA测定中进行评估。我们还建议对我们目前的先导化合物GZ-793A和本研究中出现的3-4个其他先导化合物进行综合药代动力学评估，以评估它们的可药性，以及口服给药后降低甲基苯丙胺SA的能力。我们的目标是在竞争性修订申请的第二年结束时，确定一种可用药的、口服生物可利用的临床候选药物，以便进行全面的毒理学评估，以准备向FDA提交研究性新药申请（IND）。该项目将通过额外雇用4名博士后和2名技术人员，以及通过采购额外的设备来进行研究，从而刺激经济。这个评估甲基苯丙胺阻滞剂补充系列的项目将在两年内完成。同时，母赠款将按原先提议的继续发放，因此预计母项目其余部分的预算不会有任何变化。新的资金将加快我们的工作效率，使我们能够开展这一新的但相关的调查，以期获得治疗甲基苯丙胺滥用的临床候选药物。

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.