Non-Peptidic Neuropeptide FF Receptor Probes

描述(由申请人提供)：本项目以计划公告(PA)编号：PAS-07-327提交，标题：药物滥用和成瘾化学早期职业奖(EChem)-NIDA(R03)。阿片调节多肽(强啡肽、Nociceptin、胆囊素、神经肽FF)既能降低或增强阿片类药物的药理作用，又取决于它们的剂量和作用部位。此外，这些多肽被认为是对经典阿片类药物的耐受和依赖的部分原因，经典阿片类药物是治疗中到重度疼痛最常见的处方药物类别。特别是，已经证明神经肽FF系统可能起到抗阿片系统的作用，并潜在地阻止耐受和阿片诱导的痛敏的发展。由于治疗药物滥用的策略之一是化疗，因此需要一类新的化合物作为药理探针，以帮助理解导致药物成瘾和滥用的生理机制。本研究项目的目的是寻找新的药理探针，用于研究神经肽FF系统的阿片调节特性。目前，还没有针对这种受体系统的小分子非肽探针，这极大地阻碍了对相关生理和生化作用的了解。我们在为NPFF系统设计和发现小的非肽配体方面所做的初步工作已经产生了模板，这些模板为进一步优化提供了优秀的先导化合物。我们已经确定了这一系统的激动剂和拮抗剂，但需要提高它们的亲和力。我们建议通过合成非肽性NPFF1和NPFF2配体作为激动剂或拮抗剂来实现这一点，这些配体对这些受体具有选择性或结合每个受体的亲和力。我们还将进行体外功能分析，以提供结构-活性-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分子、非肽药理探针。最终，这些探针将有助于确定与这个反阿片系统相关的药理学，并可能导致开发治疗阿片类药物添加的新疗法。 公共卫生相关性：该项目提交的计划公告(PA)编号：PAS-07-327和标题：早期职业生涯奖在药物滥用和成瘾化学(EChem)-NIDA(R03)。申请。我们已经确定了阿片调节系统的两种先导化合物(激动剂和拮抗剂)，神经肽FF。由于缺乏用于药理学研究的稳定的非肽探针，对这一拟议的反阿片系统及其在药物滥用和成瘾中的作用的研究一直受到阻碍。我们的配体可以进行结构修饰，为该体系提供第一个非肽探针。文献证明，阻断内源性系统可以减轻阿片类药物耐受和阿片类药物引起的痛觉过敏。人们非常有兴趣开发探针来研究这一系统，以进一步了解这些令人兴奋的药理学可能性。最终，这些化合物(或类似物)可能能够允许临床使用较低剂量的阿片类药物，以减少成瘾的机会。

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.