Non-Peptidic Neuropeptide FF Receptor Probes

非肽神经肽 FF 受体探针

• 批准号: 7976973
• 负责人: Christophe M Mesangeau
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976973
• 关键词: Affinity; Agonist; Award; Binding; Biochemical; Biological Assay; Chemistry; Cholecystokinin; Dependence; Development; Dose; Drug Addiction; Drug abuse; Dynorphins; Evaluation; Goals; Hyperalgesia; In Vitro; Investigation; Knowledge; Lead; Ligands; Literature; Modification; NIH Program Announcements; Narcotic Antagonists; National Institute of Drug Abuse; Opiate Addiction; Opioid; Outcome; Pain; Peptides; Pharmaceutical Preparations; Pharmacology; Physiological; Property; Qualifying; Research Project Grants; Role; Series; Site; Structure-Activity Relationship; System; Work; addiction; analog; career; chemical synthesis; chemotherapy; design; improved; interest; neuropeptide FF; neuropeptide FF receptor; nociceptin; novel; novel therapeutics; public health relevance; receptor; receptor binding

DESCRIPTION (provided by applicant): This project is submitted under Program Announcement (PA) Number: PAS-07-327 and Title: Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM) - NIDA (R03). Opioid-modulating peptides (Dynorphin, Nociceptin, Cholecystokinin, Neuropeptide FF) are able to both reduce and potentiate the pharmacological effects of opioids depending on their dose and site of action. Moreover, it has been proposed that these peptides are partially responsible for tolerance and dependence to classical opioid medications, which are the most frequently prescribed class of drugs for moderate to severe pain. In particular, it has been shown that the Neuropeptide FF system may act as an anti-opioid system and potentially block the development of tolerance and opioid-induced hyperalgesia. Since one of the strategies for treating drug abuse is chemotherapy, new classes of compounds are needed that could be utilized as pharmacological probes to aid in understanding the physiological mechanisms leading to drug addiction and abuse. The goal of this research project is to identify novel pharmacological probes useful for the investigation of the opioid- modulating properties of the Neuropeptide FF system. Currently, there are no small, non-peptide probes for this receptor system which greatly hampers the progress of understanding the associated physiological and biochemical roles. Our preliminary work on the design and discovery of small, non-peptidic ligands for the NPFF system has resulted in templates that have provided excellent lead compounds for further optimization. We have identified agonists and antagonists for this system but need to improve their affinities. We propose to accomplish this through the synthesis of non-peptidic NPFF1 and NPFF2 ligands as agonists or antagonists with selectivity for these receptors or a combination of affinities at each receptor. We will also perform in vitro functional assays to provide structure-activity-relationship information. It is anticipated that the outcome of this work will provide useful small, non-peptide pharmacological probes for the study of the NPFF system. Ultimately, these probes will help to define the pharmacology associated with this anti-opioid system and potentially lead to the development of novel therapeutics for opioid addicition. PUBLIC HEALTH RELEVANCE: This project is submitted under Program Announcement (PA) Number: PAS-07- 327 and Title: Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM) - NIDA (R03). Applications. We have identified two lead compounds (agonist and antagonist) for the opioid modulating system, Neuropeptide FF. Study of this proposed anti-opioid system and its role in drug abuse and addiction has been hampered due to the lack of stable, non-peptide probes for pharmacological study. Our ligands are amenable to structural modification to provide the first non-peptide probes for this system. It has been demonstrated in the literature that blockade of this endogenous system will alleviate opioid tolerance and opioid induced hyperalgesia. It is of high interest to develop probes to investigate this system to further understand these exciting pharmacological possibilities. Ultimately, these compounds (or analogs) might be able to allow for lower doses of clinically utilized opioids to lessen the chance of the development of addiction.

描述（由申请人提供）：该项目根据计划公告（PA）编号：PAS-07-327和标题：药物滥用与成瘾化学早期职业奖（ECHEM） - NIDA（R03）。阿片类药物调节肽（Dynorphin，NociTpin，胆囊化蛋白，神经肽FF）能够根据其剂量和作用部位减少和增强阿片类药物的药理作用。此外，已经提出，这些肽对经典阿片类药物的耐受性和依赖性部分负责，这是中度至重度疼痛的最常处方类药物。特别是，已经表明，神经肽FF系统可以充当抗阿片类系统，并有可能阻止耐受性和阿片类药物诱导的痛觉过敏的发展。由于治疗药物滥用的一种策略之一是化学疗法，因此需要将新的化合物用作药理探针，以帮助理解导致药物成瘾和滥用的生理机制。该研究项目的目的是确定可用于研究神经肽FF系统的阿片类药物调节特性有用的新型药理探针。当前，该受体系统没有小的非肽探针，这极大地阻碍了理解相关的生理和生化作用的进展。我们在针对NPFF系统的小型非肽配体设计和发现方面的初步工作，导致模板为进一步优化提供了出色的铅化合物。我们已经确定了该系统的激动剂和对手，但需要提高其亲和力。我们建议通过合成非肽NPFF1和NPFF2配体作为激动剂或拮抗剂，对这些受体选择性或每个受体的亲和力组合，以实现这一目标。我们还将执行体外功能测定，以提供结构激活关系信息。预计这项工作的结果将为NPFF系统的研究提供有用的小型非肽药理探针。最终，这些探针将有助于定义与该抗阿片类系统相关的药理学，并有可能导致新型治疗剂的阿片类药物添加剂的发展。 公共卫生相关性：该项目由计划公告（PA）编号：PAS-07-327和标题：药物滥用和成瘾化学早期职业奖（ECHEM） - NIDA（R03）。申请。我们已经确定了阿片类药物调节系统神经肽FF的两种铅化合物（激动剂和拮抗剂）。由于缺乏稳定的非肽探针进行药理学研究，对这种提出的抗阿片类药物系统及其在药物滥用和成瘾中的作用受到了阻碍。我们的配体适合结构修饰，以提供该系统的第一个非肽探针。在文献中已经证明，这种内源系统的阻塞将减轻阿片类药物的耐受性和阿片类药物诱导的痛觉过敏。开发探针以进一步了解这些令人兴奋的药理可能性是很高的兴趣。最终，这些化合物（或类似物）可能能够允许较低剂量的临床利用阿片类药物来减少成瘾的发展机会。