PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction

描述(申请人提供)：甲基苯丙胺(冰毒)成瘾是一个全球性的问题，目前在包括北卡罗来纳州在内的某些西部、中西部和南部州已经达到流行的程度。在临床上，完全戒除冰毒是非常困难的，主要是因为，即使实现了戒毒，吸毒者在多年内仍然容易受到之前与药物滥用有关的刺激所引发的渴望和复发的影响。最近的证据表明，某些蛋白激酶C(PKC)亚型(如PKC b2，y，S，z)可能在药物滥用的启动、巩固和/或长期维持中发挥重要作用。在这一点上，PKC z可能特别重要，因为这个亚型似乎介导了长时程增强(LTP)、学习和记忆的维持。我们的初步研究已经确定了几个小分子PKC z抑制剂。本项目的主要目标是设计、合成和筛选小分子文库，以鉴定和药理学评价有效的和同种异构体特异性的PKCz抑制剂作为潜在的冰毒治疗药物。首先，将对20,000个小分子进行筛选，以确定更有效和更具异构体特异性的PKC z酶活性抑制物。将建立PKC z抑制剂的构效关系(SAR)和药效团。其次，将测定HIT化合物的细胞毒性、PKC z抑制活性、有效性和特异性。第三，将评估在PKC z信号通路中选定的下游靶标对总蛋白和磷酸化水平的影响。第四，如果拟议的研究成功地发现了有效的和异构体特异性的小分子PKC z抑制剂，这些抑制剂将在冰毒敏化和自我给药模型中进行体内特异性、效力和有效性测试。这项拟议的研究代表了合成有机化学和细胞生物学的结合，以扩大冰毒成瘾的可用药理干预措施的数量，从而促进人类的长期戒除。除了拟议研究的临床意义外，它们有望为临床前阐明强迫性慢性精神刺激剂滥用和冰毒神经毒性效应的新的神经生物学机制提供新的药理学工具。公共卫生相关性：蛋白激酶C(PKC)z可能在药物滥用的启动、巩固和/或长期维持中发挥重要作用。该项目的主要目标是设计、合成和筛选小分子文库，以鉴定和药理学评价作为甲基苯丙胺(冰毒)成瘾潜在治疗剂的有效和同型特异性的PKCz抑制剂。

DESCRIPTION (provided by applicant): Methamphetamine (METH) addiction is a global problem, and has now reached epidemic proportions in certain Western, Midwestern, and Southern states including North Carolina. Total abstinence from METH is very difficult to achieve in the clinic, mainly because, even after abstinence is achieved, addicts remain vulnerable for years to episodes of craving and relapse triggered by stimuli previously associated with drug abuse. Recent evidence suggests that certain protein kinase C (PKC) isoforms (e.g., PKC b2, y, s, z) may play important roles in the initiation, consolidation and/or long-term maintenance of drug abuse. In this regard, PKC z may be particularly important because this isoform appears to mediate maintenance of long-term potentiation (LTP), learning, and memory. Our preliminary studies have identified several small molecule PKC z inhibitors. The main goals of the present project are to design, synthesize, and screen small molecule libraries to identify and pharmacologically evaluate potent and isoform-specific PKC z inhibitors as potential treatment agents for METH addiction. First, 20,000 small molecules will be screened to identify more potent and isoform-specific inhibitors of PKC z enzymatic activity. Structure-activity relationship (SAR) and pharmacophore of PKC z inhibitors will be established. Second, cellular toxicity, PKC z inhibitory activity, efficacy, and specificity of hit compounds will be determined. Third, effects on total protein and phosphorylation levels of selected downstream targets in PKC z signaling pathways will be evaluated. Fourth, if the proposed research successfully identifies potent and isoform-specific small molecule PKC z inhibitors, these inhibitors will be tested for in vivo specificity, potency, and efficacy in METH sensitization and self-administration models. The proposed research represents a combination of synthetic organic chemistry and cell biology to broaden the number of available pharmacological interventions for METH addiction and thus promote long-term abstinence in humans. In addition to the clinical significance of the proposed studies, they are expected to provide new pharmacological tools for preclinical elucidation of novel neurobiological mechanisms underlying compulsive chronic psychostimulant abuse and neurotoxic effects of METH addiction. PUBLIC HEALTH RELEVANCE: Protein kinase C (PKC) z may play important roles in the initiation, consolidation and/or long-term maintenance of drug abuse. The main goals of the proposed project are to design, synthesize, and screen small molecule libraries to identify and pharmacologically evaluate potent and isoform-specific PKC z inhibitors as potential treatment agents for methamphetamine (METH) addiction.