Development of Novel Therapeutics for Methamphetamine Abuse

目前的提案是对U 01 DA 043908“用于治疗糖尿病的新型治疗药物的开发”的补充申请。 我是“冰毒滥用”的私家侦探。甲基苯丙胺（METH）使用障碍与可怕的 健康和社会后果，其使用在美国显着增加。有效 对甲基苯丙胺使用障碍的治疗是不可用的。METH与囊泡单胺转运蛋白相互作用- 2（VMAT 2），促进多巴胺（DA）释放到胞质溶胶中，并逆转DA转运蛋白增加 细胞外DA，导致滥用倾向。该项目的重点是VMAT 2作为一种新的治疗靶点， 获得治疗METH使用障碍的总体目标。1b期研究，洛贝林，最初的铅， 完成;苦味、半衰期短和需要每日多次给药， 降低依从性。对洛贝林进行修饰以获得GZ-793 A，其具有所需的药理学，但 发现具有脱靶hERG相互作用和潜在心脏毒性。GZ-793 A的迭代优化 导致GZ-11608和JPC-077，其有效且选择性地抑制VMAT 2功能和METH- 诱发体外DA释放。重要的是，这些化合物大大降低了hERG活性， 证明了我们进一步修饰分子以消除脱靶相互作用的能力。这些类似物还 在大鼠中特异性减少METH自我给药和METH诱导的恢复，剂量不 改变食物强化。重复给药后未出现耐受性。这些类似物也保护了 对抗或不加剧甲基苯丙胺诱导的纹状体DA神经毒性。尽管这种有利的药理学 这些类似物的口服生物利用度较低（大鼠中F% = 3%）。当前项目（U 01 DA 043908） 产生优化的GZ-11608类似物。同样，我们达到了里程碑，并确定了一个非常有前途的 化合物STK-5-25，在VMAT 2处Ki = 19 nM，未检测到hERG相互作用，在大鼠中稳定性>4 h 微粒体和F% = 30%。目前的铅STK-5-25在其中一个环上具有苯胺部分， 可能与特异质肝毒性相关，生物转化为活性代谢物，尽管我们有 未观察到大鼠肝酶的变化。我们对所要求的补充资金的计划是 含氮杂环取代苯胺作为候选和备份的最终优化策略 在3个种属中开展IND使能研究。为此，我们将聘请合同研究组织（CRO）， 在活动奖励期的最后几个月合成50-100种化合物。化合物将 在体外药理学试验中进行评价，以告知活性期间合成的优先顺序 目前的奖项。药代动力学和行为分析的评价将在免费期间进行。 延长期。因此，我要求NIDA提供补充资金，以便我们能够最终确定 优化我们的先导化合物，并带着新的GOMD申请回来，使我们能够提交IND申请 目的是开发一种治疗甲基苯丙胺使用障碍的药物。

The current proposal is a request for a supplement to U01 DA043908 “Development of Novel Therapeutics for Methamphetamine Abuse” on which I serve as PI. Methamphetamine (METH) use disorder is linked to dire health and societal consequences and its use has markedly increased in the United States. Effective treatments for METH use disorder are not available. METH interacts with the vesicular monoamine transporter- 2 (VMAT2), promoting dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA, resulting in abuse liability. This project focuses on VMAT2 as a novel therapeutic target, with the overall goal of obtaining a treatment for METH use disorder. Phase 1b studies with lobeline, the initial lead, were completed; bitter taste, short half-life and the requirement for multiple daily doses were expected to reduce compliance. Lobeline was modified to obtain GZ-793A, which had the desired pharmacology, but was found to have off-target hERG interaction and potential cardiotoxicity. Iterative optimization of GZ-793A resulted in GZ-11608 and JPC-077, which were potent and selective inhibiting VMAT2 function and METH- evoked DA release in vitro. Importantly, these compounds had greatly reduced hERG activity, and demonstrated our ability to further modify the molecule to eliminate off-target interactions. These analogs also specifically decreased METH self-administration and METH-induced reinstatement in rats, at doses that did not alter food reinforcement. Tolerance did not develop upon repeated dosing. These analogs also protected against or did not exacerbate METH-induced striatal DA neurotoxicity. Despite this favorable pharmacologic profile, these analogs had low oral bioavailability (F% = 3% in rats). The current project (U01 DA043908) produced optimized GZ-11608 analogs. Again, we met the milestones and identified a very promising compound, STK-5-25, that has a Ki = 19 nM at VMAT2, no detectable hERG interaction, >4 h stability in rat microsomes and F% = 30% in rats. The current lead STK-5-25 has an aniline moiety on one of the rings, which can be associated with idiosyncratic liver toxicity with bioconversion to a reactive metabolite, although we have not observed changes in liver enzymes in rats. Our plan for the requested supplemental funds is to substitute nitrogenous heterocycles in place of the aniline as a final optimization strategy for a candidate and backup for IND enabling studies in 3 species. To do this we will employ a Contract Research Organization (CRO) to synthesize 50-100 compounds during the last few months of the active award period. Compounds will be evaluated in in vitro pharmacological assays to inform the prioritization of synthesis during the active period of the current award. Evaluation in pharmacokinetic and behavioral assays will proceed during the no cost extension period. Thus, I am requesting that NIDA provide supplemental funding, so that we can finalize the optimization of our lead compound and come back with a new GOMD application to bring us to IND submission with the goal of developing a pharmacotherapy for methamphetamine use disorder.