Optimization of non-peptide probes for the NPFF receptor system

NPFF受体系统非肽探针的优化

• 批准号: 8927596
• 负责人: Christopher R McCurdy
• 金额: $ 48.58万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927596
• 关键词: Acute; Adverse effects; Affinity; Agonist; Analgesics; Area; Attenuated; Biological Assay; Biological Availability; Brain; Cell Membrane Permeability; Chemicals; Cholecystokinin; Chronic; Clinical; Communities; Dependence; Development; Dose; Dose-Limiting; Drug Addiction; Drug Kinetics; Drug abuse; Evaluation; Goals; Half-Life; Health; Hyperalgesia; In Vitro; Laboratories; Lead; Ligands; Literature; Measures; Mediating; Medical; Metabolic; Modeling; Modification; Mus; NIH Program Announcements; Narcotic Antagonists; Opioid; Opioid Peptide; Opioid Receptor; Oral Administration; Pain; Peptides; Perception; Pharmaceutical Preparations; Pharmacology; Plasma; Preparation; Property; Protein Binding; Rattus; Recording of previous events; Reporting; Research; Rewards; Role; Site; Solubility; Structure-Activity Relationship; System; Tail; Testing; Time; Water; Withdrawal; Work; addiction; chemical synthesis; endogenous opioids; in vitro Assay; in vivo; neuropeptide FF; neuropeptide FF receptor; novel; receptor; receptor binding; screening; small molecule; therapeutic target; tool

DESCRIPTION (provided by applicant): This project is submitted under Program Announcement (PA) Number: PAR-12-060 and Title: Solicitation of Validated Hits for the Discovery of in vivo Chemical Probes (R01). Opioid receptors are well known to be intimately involved with modulating the perception of pain. Throughout history, opioid preparations have been utilized to effectively manage pain and have continued to be the mainstay of therapy due to their efficacy. However, these drugs are associated with the liabilities of dose-limiting side-effects, tolerance and addiction. Still they are the most widely prescribed medications to treat acute and chronic severe pain. The search for an effective analgesic compound devoid of side-effects, is still a large goal of the medical establishment. Only recently in history was it realizd that endogenous opioid-modulating peptides exist that can be utilized as a means of additional therapy to attenuate these liabilities. These opioid modulating peptides (specifically cholecystokinin and Neuropeptide FF) are able to both reduce and potentiate the pharmacological effects of opioids depending on the dose and site of action. More interestingly, they have been proposed to have a role and possible responsibility for tolerance and dependence associated with opioid therapy. Specifically, Neuropeptide FF (NPFF) has been reported to exist as an endogenous anti-opioid system and block the development of tolerance and opioid-induced hyperalgesia. There are two recognized receptors in this system, NPFF1 and NPFF2. Currently, established (subtype selective or non-selective) small molecule, non-peptide probes for the NPFF system do not exist. This lack of a suitable non-peptide probe has hampered the full understanding of the actions of NPFF and how this receptor system is involved in the actions of opioids as well as other proposed pharmacologies. It is the goal of this project to identify one or more suitable non-peptide probes to serve the research community in an effort to further characterize the NPFF system. Our lead molecules, generated under our project R03 DA029738, show that we have both angonists and antagonists for this system and have begun to understand selectivity issues yet they need to be optimized for in vivo approaches. This work will be carried out through the following specific aims: AIM 1 - To prepare through chemical synthesis, novel non-peptidic NPFF1 and NPFF2 ligands, agonists or antagonists with selectivity for NPFF1, NPFF2, or a combination of affinities at each receptor; AIM 2 - To investigate the physiochemical properties of high affinity NPFF ligands through a variety of in vitro assays that will assess solubility, stability, membrane permeability, protein binding, microsomal stability and metabolic profiling; AIM 3 - To perform in vivo pharmacokinetics in rats to determine half-life, bioavailability and brain to plasma ratios. Those compounds that show activity will be subjected to full PK workup in rats to ultimately determine their suitability as potential in vivo probes and to understand their dosing requirements (peak time, brain:plasma, half-life, clearance); AIM 4 - To evaluate novel NPFF ligands in vivo for hyperalgesic activity. Compounds will be evaluated in a warm-water tail-withdrawal hyperalgesia model to confirm and further determine pharmacological profiles of those compounds identified in Aims 2 and 3. Overall, with our expertise through this project, we will provide the research community with suitable in vivo non-peptide probes to further characterize the NPFF system. These will be new tools as currently, non-peptide NPFF ligands with favorable affinities, activities, and in vivo properties do not exist.

描述（由申请人提供）：此项目由计划公告（PA）编号：PAR-12-060和标题：征集经过验证的命中以发现体内化学探针（R01）。众所周知，阿片类药物受体与调节疼痛的感知密切相关。在整个历史上，阿片类药物的制剂都被用来有效地管理疼痛，并且由于其功效而继续成为治疗的主要手段。但是，这些药物与剂量限制副作用，耐受性和成瘾的负债有关。仍然是治疗急性和慢性严重疼痛的最广泛规定的药物。寻找没有副作用的有效镇痛化合物仍然是医疗机构的重大目标。直到历史上，才知道存在内源性阿片类药物调节肽，可以用作衰减这些责任的额外疗法的一种手段。这些阿片类药物调节肽（特别是胆囊动蛋白和神经肽FF）能够根据剂量和作用部位减少和增强阿片类药物的药理作用。更有趣的是，他们被提议对与阿片类药物疗法相关的宽容和依赖性负有角色和可能的责任。具体而言，据报道，神经肽FF（NPFF）作为内源性抗阿片类系统存在，并阻止耐受性和阿片类药物诱导的痛觉过敏的发展。该系统中有两个公认的受体NPFF1和NPFF2。当前，不存在NPFF系统的非肽探针（亚型选择性或非选择性）小分子。缺乏合适的非肽探针阻碍了对NPFF作用以及该受体系统如何参与阿片类药物以及其他提出的药理作用的全部理解。这是目标的目标 项目旨在识别一种或多种合适的非肽探针，以服务研究界，以进一步表征NPFF系统。我们的铅分子在我们的项目R03 DA029738下产生的，表明我们既有该系统的angonists and Antoganists and Antoganists and Antoganist and Antoggoganist and，又开始理解选择性问题，但需要针对体内方法进行优化。这项工作将通过以下特定目的进行：目标1-通过化学合成，新型的非肽NPFF1和NPFF2配体，具有选择性的NPFF1，NPFF2，NPFF2或每个受体亲和力组合的激动剂或拮抗剂的准备； AIM 2-通过多种体外测定法研究高亲和力NPFF配体的生理化学特性，这些测定方法将评估溶解度，稳定性，膜通透性，蛋白质结合，微粒体稳定性和代谢分布；目标3-在大鼠中进行体内药代动力学，以确定半衰期，生物利用度和大脑与血浆比率。那些显示活性的化合物将在大鼠中进行完整的PK工作，以最终确定其作为体内探针潜在的适合性并了解其剂量要求（高峰时间，大脑：等离子体，血浆，半寿命，清除）； AIM 4-在体内评估新型NPFF配体的高过敏活性。化合物将在温水尾流的痛痛模型中进行评估，以确认和进一步确定AIMS 2和3中确定的化合物的药理学特征。总体而言，通过该项目，我们将为研究社区提供合适的无体内非肽探针，以进一步表征NPFF系统。这些将是当前的新工具，即具有良好亲和力，活动和体内特性的非肽NPFF配体。