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）已达到流行病的程度。在临床上很难完全戒除甲基苯丙胺，这主要是因为，即使在戒除之后，成瘾者多年来仍然容易受到以前与药物滥用有关的刺激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（例如，PKC b2，y，s，z）可能在药物滥用的启动、巩固和/或长期维持中起重要作用。在这方面，PKC z可能是特别重要的，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，以鉴定和评价作为METH成瘾的潜在治疗剂的有效和亚型特异性PKC z抑制剂。首先，将筛选20，000个小分子，以鉴定PKC z酶活性的更有效和亚型特异性抑制剂。建立PKC z抑制剂的构效关系和药效团。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点的总蛋白和磷酸化水平的影响。第四，如果拟议的研究成功地鉴定出有效的和亚型特异性的小分子PKC z抑制剂，则将在METH致敏和自我给药模型中测试这些抑制剂的体内特异性、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METH成瘾的可用药理学干预措施的数量，从而促进人类的长期戒断。除了临床意义的拟议研究，他们预计将提供新的药理学工具，临床前阐明新的神经生物学机制的强迫性慢性精神兴奋剂滥用和神经毒性作用的甲基成瘾。公共卫生关系：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，以鉴定和评价作为甲基苯丙胺（METH）成瘾潜在治疗药物的强效和亚型特异性PKC z抑制剂。