Non-Peptidic Neuropeptide FF Receptor Probes

描述（由申请人提供）：本项目是根据计划公告（PA）编号：PAS-07-327和标题：早期职业奖在药物滥用和成瘾化学（ECHEM）- NIDA（R 03）提交的。阿片类调节肽（强啡肽、孤啡肽、胆囊收缩素、神经肽FF）能够根据其剂量和作用部位降低和增强阿片类药物的药理学作用。此外，已经提出这些肽部分地负责对经典阿片类药物的耐受性和依赖性，经典阿片类药物是用于中度至重度疼痛的最常见的处方类药物。特别地，已经显示神经肽FF系统可以充当抗阿片系统并且潜在地阻断耐受性和阿片诱导的痛觉过敏的发展。由于治疗药物滥用的策略之一是化疗，因此需要新的化合物类别，其可用作药理学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确定新的药理学探针用于研究神经肽FF系统的阿片调节特性。目前，还没有小的，非肽探针的这种受体系统，极大地阻碍了了解相关的生理和生化作用的进展。我们在设计和发现用于NPFF系统的小的非肽配体方面的初步工作已经产生了为进一步优化提供优良的先导化合物的模板。我们已经确定了该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NPFF 1和NPFF 2配体作为对这些受体具有选择性的激动剂或拮抗剂或对每种受体具有亲和力的组合来实现这一点。我们还将进行体外功能测定，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的非肽药理学探针。最终，这些探针将有助于定义与这种抗阿片系统相关的药理学，并可能导致阿片类药物成瘾的新疗法的开发。 公共卫生相关性：该项目是根据计划公告（PA）编号：PAS-07- 327和标题提交的：药物滥用和成瘾化学（ECHEM）- NIDA（R 03）早期职业奖。应用.我们已经确定了两个先导化合物（激动剂和拮抗剂）的阿片调节系统，神经肽FF。由于缺乏稳定的非肽类探针用于药理学研究，对这种拟议的抗阿片系统及其在药物滥用和成瘾中的作用的研究受到阻碍。我们的配体适合于结构修饰，以提供用于该系统的第一个非肽探针。在文献中已经证明，阻断该内源性系统将减轻阿片耐受和阿片诱导的痛觉过敏。开发探针来研究该系统以进一步了解这些令人兴奋的药理学可能性是非常有趣的。最终，这些化合物（或类似物）可能能够允许较低剂量的临床使用的阿片类药物，以减少成瘾发展的机会。

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.