Small Molecule Identification for the Nociceptin Receptor to Treat Cocaine Abuse

治疗可卡因滥用的伤害感受素受体的小分子鉴定

• 批准号: 8468158
• 负责人: Claes Robert Wahlestedt
• 金额: $ 33.62万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468158
• 关键词: Affinity; Agonist; Alcohols; Binding; Biological Assay; Cells; Clinical; Cocaine; Cocaine Abuse; Cocaine Dependence; Coupling; Data; Dependence; Development; Disease; Drug Receptors; Evaluation; Future; GTP-Binding Proteins; Goals; Health; Housing; In Vitro; Instruction; Lead; Life; Ligands; MAPK8 gene; Mediating; Molecular; Nicotine; Opioid Receptor; Pathway interactions; Peptides; Pharmacology; Pharmacotherapy; Physiological; Physiology; Program Development; Program Research Project Grants; Publishing; Receptor Activation; Receptor Signaling; Research; Rewards; Role; Signal Pathway; Signal Transduction; Societies; Staging; Substance Addiction; Substance of Abuse; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Validation; Work; addiction; base; beta-arrestin; cocaine receptor; cocaine use; counterscreen; cytotoxicity; delta opioid receptor; design; mu opioid receptors; new therapeutic target; nociceptin; nociceptin receptor; novel; novel therapeutics; pre-clinical; receptor; small molecule; tool

The overall and specific goal of this application is the identification of novel high affinity and selective functional agonists of the nociceptin receptor that can be used to treat cocaine addiction. In previous efforts, we have identified, designed and synthesized novel, potent, and selective nociceptin receptor (a.k.a. ORL-1, NOP) agonists as tools for research on substance dependence with potential as clinically effective therapeutic agents. The disease target, cocaine abuse, represents an enormous health burden on society and for which currently available pharmacotherapies have insufficient efficacy. We propose nociceptin receptor agonism as a mechanism to achieve the therapeutic objective. Studies suggest that nociceptin activation opposes the dependence effects of substances of abuse such as nicotine, alcohol and cocaine. We propose nociceptin receptor activation as a mechanism to achieve the therapeutic objective of reduced cocaine addiction. While no clinical validation exists for the mechanism, the hypothesis supported by preclinical data, and would benefit from directed studies using optimized ligands, such as those we propose, to uncover the contributions of the nociceptin receptor to cocaine abuse as the first steps in developing novel therapeutics. In this application, we extend this molecule development program to center on the design, synthesis and evaluation of agents for that can be used in cocaine addiction research with potential to become therapeutics based on their actions at the nociceptin receptor. The pharmacology of novel compounds will be assessed in multiple cell-based assays and will include opioid receptor counterscreens to routinely determine potency and selectivity at a very early stage. The compound starting points for this project show no addictive potential, and a high level of selectivity over the mu opioid receptor, an improvement over currentiy available NOP agonists. This application is aimed at the development of the idea that nociceptin receptor agonists can be used to treat cocaine abuse. RELEVANCE (See instructions): Cocaine use represents an enormous worldwide health burden, in the US alone in 2009 more than 4.8 million people abused cocaine. Current cocaine use therapies are simply not effective and novel therapeutics are greatly needed. This project will test the hypothesis that the nociceptin receptor is involved in cocaine reward pathways in an attempt to validate the nociceptin receptor as a target for novel therapeutics to treat cocaine abuse.

本申请的总体和具体目标是鉴定新的高亲和力和 可用于治疗可卡因的伤害素受体的选择性功能激动剂 上瘾。在之前的努力中，我们已经识别、设计和合成了新的、有效的和 选择性伤害素受体(又名Orl-1，NOP)激动剂作为物质研究的工具 有潜力成为临床有效的治疗药物的依赖性。疾病的目标，可卡因 虐待，是社会的巨大健康负担，目前可以用来治疗 药物治疗的效果不够好。我们建议伤害素受体激动剂作为一种 达到治疗目的的机制。研究表明，伤害素激活 反对尼古丁、酒精和可卡因等滥用物质的依赖效应。 我们建议将伤害素受体激活作为实现治疗目标的机制。 减少了可卡因成瘾。虽然目前还没有对这种机制进行临床验证，但 假说得到临床前数据的支持，并将受益于使用 优化的配体，如我们提出的那些，以揭示伤害素的贡献 将受体与可卡因滥用联系起来，作为开发新疗法的第一步。在此应用程序中， 我们将这一分子开发计划扩展到以设计、合成和 可用于可卡因成瘾研究的试剂的评估有可能成为 基于它们在伤害素受体上的作用的治疗学。小说的药理学 化合物将在多个基于细胞的分析中进行评估，并将包括阿片受体 在非常早的阶段进行常规的反筛选以确定效力和选择性。这个 这个项目的复合起点没有表现出上瘾的潜力，而且高水平的 对u阿片受体的选择性，比目前可用的NOP激动剂有所改善。 这项应用旨在发展伤害素受体激动剂可以 被用来治疗可卡因滥用。 相关性(请参阅说明)： 可卡因的使用代表着巨大的全球健康负担，仅在美国2009年就超过4.8 数百万人滥用可卡因。目前的可卡因使用疗法根本不是有效的和新的疗法 是非常需要的。这个项目将检验伤害素受体与可卡因有关的假设。 尝试验证伤害素受体作为新疗法治疗靶点的奖励途径 可卡因滥用。