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（甲基苯丙胺）成瘾是一个全球问题，现在已经在包括北卡罗来纳州在内的某些西部，中西部和南部各州达到了流行比例。在诊所中，难以实现甲基苯酚的完全禁欲，主要是因为即使实现了禁欲，成瘾者也很容易受到渴望发作的危害，并由先前与药物滥用相关的刺激引起的复发。最近的证据表明，某些蛋白激酶C（PKC）同工型（例如PKC B2，Y，S，Z）可能在开始，合并和/或长期维持药物滥用方面起重要作用。在这方面，PKC Z可能尤其重要，因为这种同工型似乎可以介导长期增强（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，合成和筛选小分子库，以识别和药理评估有效和同工型特异性的PKC Z抑制剂，作为甲基成瘾的潜在治疗剂。首先，将筛选20,000个小分子，以鉴定PKC Z酶活性的更有效和同工型特异性抑制剂。将建立PKC Z抑制剂的结构活性关系（SAR）和药效团。其次，将确定细胞毒性，PKC Z抑制活性，功效和命中化合物的特异性。第三，将评估对PKC Z信号通路中选定下游靶标的总蛋白质和磷酸化水平的影响。第四，如果拟议的研究成功地鉴定了有效和同工型特异性的小分子PKC Z抑制剂，则将对这些抑制剂进行体内特异性，效能和疗效，以甲基化和自我加热模型进行测试。拟议的研究代表了合成有机化学和细胞生物学的结合，以扩大可用的药理学干预措施的甲基成瘾措施，从而促进人类的长期禁欲。除了拟议的研究的临床意义外，他们还有望提供新的药理学工具，用于临床前阐明强迫性的慢性精神刺激性滥用和甲基成瘾的神经毒性作用的新型神经生物学机制。公共卫生相关性：蛋白激酶C（PKC）Z可能在吸毒滥用的启动，巩固和/或长期维持中起重要作用。拟议项目的主要目标是设计，合成和筛选小分子库，以识别和药理评估有效的和同工型特异性的PKC Z抑制剂，作为甲基苯丙胺（METH）成瘾的潜在治疗剂。