PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction

用于治疗甲基苯丙胺成瘾的 PKC zeta 特异性抑制剂

• 批准号: 7641187
• 负责人: Jiyong Hong
• 金额: $ 19.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641187
• 关键词: AMPA Receptors; Abstinence; Acute; Address; Affect; Biological Assay; Biological Markers; Cell Survival; Cells; Cellular biology; Chronic; Clinic; Cocaine; Docking; Drug abuse; Epidemic; Exhibits; Extinction (Psychology); Goals; Homosynaptic Depression; Human; Intervention; Learning; Literature; Long-Term Potentiation; Maintenance; Mediating; Memory; Methamphetamine; Modeling; Molecular; North Carolina; Nucleus Accumbens; Organic Chemistry; PC12 Cells; Pathway Analysis; Pattern; Pharmaceutical Preparations; Phosphorylation; Play; Pre-Clinical Model; Prefrontal Cortex; Protein Isoforms; Protein Kinase C; Protein Kinase C Inhibitor; Relapse; Research; Role; Schedule; Self Administration; Signal Pathway; Specificity; Stimulus; Structure-Activity Relationship; Testing; Toxic effect; Treatment Protocols; addiction; base; citrate carrier; clinically significant; craving; design; in vivo; inhibitor/antagonist; neurobiological mechanism; neurochemistry; neurotoxic; novel; pharmacophore; pre-clinical; protein kinase C zeta; public health relevance; scaffold; small molecule; small molecule libraries; stimulant abuse; tool

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.

描述（由申请人提供）：甲基苯丙胺 (METH) 成瘾是一个全球性问题，目前在某些西部、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，即使在戒除之后，成瘾者在多年内仍然容易因先前与药物滥用相关的刺激而引发渴望和复发。最近的证据表明，某些蛋白激酶 C (PKC) 亚型（例如 PKC b2、y、s、z）可能在药物滥用的起始、巩固和/或长期维持中发挥重要作用。在这方面，PKC z 可能特别重要，因为这种亚型似乎介导长时程增强 (LTP)、学习和记忆的维持。我们的初步研究已经鉴定出几种小分子 PKC z 抑制剂。本项目的主要目标是设计、合成和筛选小分子库，以鉴定和药理学评估有效的异构体特异性 PKC z 抑制剂作为冰毒成瘾的潜在治疗药物。首先，将筛选 20,000 种小分子，以确定更有效的 PKC z 酶活性抑制剂。将建立 PKC z 抑制剂的构效关系 (SAR) 和药效团。其次，将确定命中化合物的细胞毒性、PKC z 抑制活性、功效和特异性。第三，将评估对 PKC z 信号通路中选定下游靶标的总蛋白和磷酸化水平的影响。第四，如果拟议的研究成功鉴定出有效的异构体特异性小分子 PKC z 抑制剂，这些抑制剂将在 METH 致敏和自我给药模型中测试体内特异性、效力和功效。拟议的研究代表了合成有机化学和细胞生物学的结合，以扩大可用于冰毒成瘾的药物干预措施的数量，从而促进人类的长期戒断。除了拟议研究的临床意义外，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背后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 可能在药物滥用的引发、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、合成和筛选小分子库，以鉴定和药理学评估有效的异构体特异性 PKC z 抑制剂作为甲基苯丙胺 (METH) 成瘾的潜在治疗药物。