Development of Novel Therapeutics for Methamphetamine Abuse

甲基苯丙胺(冰毒)使用障碍与严重的健康和社会后果有关。有效治疗- 目前还没有针对冰毒成瘾的药物。冰毒与囊泡单胺转运体-2相互作用 (VMAT2)，促进多巴胺(DA)释放到胞浆中，并逆转DA转运体，以增加ex. 细胞DA，导致滥用责任。该项目将VMAT2作为一种新的治疗靶点， 总体目标是获得冰毒使用障碍的治疗。1b期研究洛贝林，最初的先导， 已经完成；然而，苦味和每日多次服药预计会降低遵从性。Lobeline 经修饰得到GZ-793A，既有理想的药理作用，又有HERG毒性。我们是下一个 鉴定出了新的小分子GZ-11608和JPC-077，它们的HERG相互作用大大减弱，并且与PO-2的相互作用大大减弱。 对VMAT2功能和甲基诱发的DA释放的选择性抑制作用。这些新线索特别是 在不改变食物的剂量下减少大鼠的冰毒自我给药和冰毒诱导的恢复 强化，提示预防复发的功效。反复给药不会产生耐受性。这些 类似物可保护或不加重冰毒诱导的纹状体DA神经毒性。尽管有这样的有利条件 药理方面，这些类似物口服生物利用度较低。因此，本提案的重点是Discov- 查询/开发优化的GZ-11608和JPC-077类似物，提高口服生物利用度。首先，我们将 在易受代谢影响的部位用重氢代替氢。如果代氚不成功，我们将 将使用合理的设计，根据每一条线索合成一个聚焦的库。化学信息学，合并 基于我们的~520个VMAT2靶向化合物的精炼模型被用于预测优化的Ana-A。 具有更低的新陈代谢倾向和理想的药物性质的原木。每一种类似物，都来自于代氢材料- 此外，还将合成TUTION和MEDCHEM方法，并对其选择性抑制VMAT2进行评估 作为新陈代谢。然后我们将评估药物动力学(PK)以确定口服生物利用度、血浆和 静脉、PO和SC给药后的脑血药浓度和估计PK参数。代谢物超过10% 将被合成并评估其毒性和作为活性药物成分的潜在用途。我们会 然后确定冰毒自我给药和恢复的剂量相关抑制。TOL的发展-- 重复给药后的误差将被确定。我们将进行简短的毒理学研究 并评估脱靶相互作用和CYP450抑制/诱导的可能性。我们会把药品-- 优化的类似物的协同动力学药效作用，并确定最大耐受量，治疗。 治疗指数和行为特异性。这一优化计划的完成将允许立即传输 将我们的线索放在支持IND的研究中。该项目的成功完成应该会有巨大的 对社会有益的健康和社会经济影响，因为目前没有可用的治疗方法 冰毒使用障碍。

Methamphetamine (METH) use disorder is linked to dire health and societal consequences. Effective treat- ments for METH addiction 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 ex- tracellular 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; however, bitter taste and multiple daily doses were expected to reduce compliance. Lobeline was modified to obtain GZ-793A, which had the desired pharmacology, but also had hERG toxicity. We next identified novel small molecules, GZ-11608 and JPC-077, with greatly reduced hERG interaction, and with po- tent and selective inhibition of VMAT2 function and METH-evoked DA release. These new leads specifically decrease METH self-administration and METH-induced reinstatement in rats at doses that do not alter food reinforcement, suggesting efficacy against relapse. Tolerance does not develop upon repeated dosing. These analogs protect against or do not exacerbate METH-induced striatal DA neurotoxicity. Despite this favorable pharmacologic profile, these analogs have low oral bioavailability. Thus, this proposal focuses on the discov- ery/development of optimized GZ-11608 and JPC-077 analogs with increased oral bioavailability. First, we will substitute deuterium for hydrogen at sites of metabolic liability. If deuterium substitution is not successful, we will use rational design to synthesize a focused library based on each lead. Chemoinformatics, incorporating refined models based on our library of ~520 VMAT2-targeted compounds, was used to predict optimized ana- logs with decreased metabolic liability and desirable drug-like properties. Each analog, from deuterium substi- tution and medchem approaches, will be synthesized and evaluated for selective inhibition of VMAT2, as well as metabolism. We will then assess the pharmacokinetics (PK) to determine oral bioavailability, plasma and brain concentrations and estimate PK parameters following IV, PO and SC dosing. Metabolites exceeding 10% will be synthesized and evaluated for toxicity and potential use as active pharmaceutical ingredient. We will then determine the dose-related inhibition of METH self-administration and reinstatement. Development of tol- erance following repeated administration will be determined. We will conduct abbreviated toxicology studies and assess the potential for off-target interactions and CYP450 inhibition/induction. We will relate the pharma- cokinetics of optimized analogs to pharmacodynamic effects, and determine the maximum tolerated dose, ther- apeutic index and behavioral specificity. Completion of this optimization program will allow for immediate tran- sition of our leads into IND-enabling studies. Successful completion of the project should have a tremendously beneficial health and socioeconomic impact on society, since currently there are no available treatments for METH use disorder.