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: 8462352
• 负责人: Claes Robert Wahlestedt
• 金额: $ 35.94万
• 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/8462352
• 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高亲和力的寡核苷酸。 可用于治疗可卡因的痛敏素受体的选择性功能激动剂 成瘾在以前的努力中，我们已经确定，设计和合成了新的，有效的， 选择性痛敏素受体（a.k.a. ORL-1，NOP）激动剂作为物质研究的工具 依赖性，具有作为临床有效治疗剂的潜力。疾病的目标，可卡因 滥用，对社会造成巨大的健康负担，目前可用的 药物疗法的功效不足。我们建议痛敏素受体激动剂作为一种 实现治疗目标的机制。研究表明， 对抗尼古丁、酒精和可卡因等滥用物质的依赖性。 我们提出痛敏素受体激活作为一种机制，以实现治疗目标 减少可卡因成瘾。虽然该机制没有临床验证， 假设得到临床前数据的支持，并将受益于使用 优化配体，如我们提出的，以揭示伤害感受素的贡献， 作为开发新疗法的第一步。在本申请中， 我们将这个分子开发计划扩展到以设计，合成和 评估可用于可卡因成瘾研究的药物， 基于它们对痛敏素受体的作用的治疗剂。小说的药理学 化合物将在多种基于细胞的测定中进行评估，其中包括阿片受体 在非常早期的阶段进行常规的效价和选择性测定。的 该项目的复合起点显示没有上瘾的潜力， 相对于μ阿片受体的选择性，相对于目前可用的NOP激动剂的改进。 本申请的目的是发展这样的想法，即痛敏素受体激动剂可以 用于治疗可卡因滥用。 相关性（参见说明）： 可卡因的使用是一个巨大的全球健康负担，仅在美国，2009年就超过4.8 100万人滥用可卡因。目前的可卡因使用疗法根本不是有效的和新的治疗方法 非常需要。这个项目将测试的假设，伤害感受素受体参与可卡因 奖励途径，试图验证痛敏素受体作为新疗法的靶点， 可卡因滥用