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: 8652971
• 负责人: Claes Robert Wahlestedt
• 金额: $ 33.95万
• 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/8652971
• 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.

本应用的总体和具体目标是识别新型高亲和力和 可用于治疗可卡因的Nociteptin受体的选择性功能激动剂 瘾。在以前的努力中，我们已经确定，设计和合成了小说，有效和 选择性nocceptin受体（又称OR​​L-1，NOP）激动剂作为研究物质的工具 具有临床有效治疗剂的依赖性。疾病靶标，可卡因 虐待，代表了社会的巨大健康负担，目前可用 药物治疗的功效不足。我们提出了nocceptin受体激动剂作为一种 实现治疗目标的机制。研究表明，诺西特蛋白激活 反对滥用物质的依赖性影响，例如尼古丁，酒精和可卡因。 我们提出了Nocteptin受体激活，作为实现治疗目标的机制 可卡因成瘾减少。尽管该机制不存在临床验证，但 临床前数据支持的假设，将受益于使用的定向研究 优化的配体，例如我们建议的配体，以揭示NociTptin的贡献 可卡因滥用的受体是发展新型治疗剂的第一步。在此应用程序中 我们将此分子开发计划扩展到设计，合成和 可以评估剂的代理人可以在可卡因成瘾研究中使用，并有可能成为 治疗剂基于它们在诺耐粘体受体中的作用。新颖的药理学 化合物将在多个基于细胞的测定中进行评估，并包括阿片类药物受体 反屏幕以常规确定在很早的阶段的效力和选择性。这 该项目的复合起点没有令人上瘾的潜力，并且很高 对MU阿片类药物受体的选择性，对当前可用的NOP激动剂的改善。 该应用旨在发展nocItptin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）： 可卡因的使用代表了全球巨大的健康负担，仅在2009年美国，可卡因超过4.8 百万人滥用可卡因。当前的可卡因使用疗法根本无效且新颖的治疗疗法 非常需要。该项目将检验nocceptin受体参与可卡因的假设 奖励途径试图验证诺耐粘蛋白受体作为治疗新疗法的靶标 可卡因滥用。