PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction

描述（由申请人提供）：甲基苯丙胺（冰毒）成瘾是一个全球性问题，现在在某些西部、中西部和南部州（包括北卡罗来纳州）已达到流行病的程度。在临床中完全戒断冰毒是非常困难的，主要原因是，即使戒断了冰毒，成瘾者在数年内仍然很容易受到先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）异构体（例如PKC b2， y, s, z）可能在药物滥用的开始，巩固和/或长期维持中发挥重要作用。在这方面，pkcz可能特别重要，因为这种异构体似乎介导长期增强（LTP）、学习和记忆的维持。我们的初步研究已经确定了几种小分子pkcz抑制剂。本项目的主要目标是设计、合成和筛选小分子文库，以鉴定和药理学评估有效的和同型特异性PKC z抑制剂作为冰毒成瘾的潜在治疗剂。首先，将筛选20,000个小分子，以确定更有效的PKC z酶活性的同工异构体特异性抑制剂。建立pkcz抑制剂的构效关系（SAR）和药效团。其次，细胞毒性、pkcz抑制活性、功效和特异性将被确定。第三，将评估PKC z信号通路中选定下游靶点对总蛋白和磷酸化水平的影响。第四，如果提出的研究成功地鉴定出有效的和同型特异性的PKC z小分子抑制剂，这些抑制剂将在甲基苯丙胺致敏和自我给药模型中测试体内特异性、效力和有效性。拟议的研究代表了合成有机化学和细胞生物学的结合，以扩大对冰毒成瘾的可用药理学干预的数量，从而促进人类的长期戒断。除了提出的研究的临床意义外，它们还有望为临床前阐明强迫性慢性精神兴奋剂滥用和冰毒成瘾的神经毒性作用的新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可能在药物滥用的开始、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，以鉴定和药理学评估有效的和同型特异性PKC z抑制剂作为甲基苯丙胺（METH）成瘾的潜在治疗剂。

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.