Selectively Targeting Opioid Receptor Heterodimers

选择性靶向阿片受体异二聚体

• 批准号: 8225136
• 负责人: Pamela Michael England
• 金额: $ 9.29万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225136
• 关键词: Acute Pain; Affinity; Agonist; Alcohol consumption; Animals; Binding; Cell Line; Cells; Complex; Data; G-Protein-Coupled Receptors; Goals; Heterodimerization; In Vitro; Intervention; Knock-out; Knockout Mice; Ligands; Molecular; NIH Program Announcements; Nature; Nociception; Opioid; Opioid Receptor; Pharmaceutical Preparations; Pharmacology; Property; Research; Role; Series; System; Testing; abstracting; addiction; alcoholism therapy; base; chronic pain; design; drinking; high risk; in vivo; innovation; kappa opioid receptors; monomer; mu opioid receptors; novel; pharmacophore; public health relevance; receptor; tool

DESCRIPTION (provided by applicant): Selectively Targeting Opioid Receptor Heterodimers 7. Project Summary/Abstract Opioid receptors are important targets for the treatment of acute and chronic pain indications and are one of the few targets currently subject to pharmacological intervention in the treatment of alcoholism. The opioid receptor system is comprised of three highly related receptors: the mu, delta, and kappa opioid receptors (MOR, DOR, and KOR respectively). Studies using knock-out animals have demonstrated that each of these receptors has a unique contribution to nociception and alcohol consumption. Despite more than 50 years of research, several mysteries remain as to the pharmacology of the opioid receptors. In particular, there are pharmacologically-defined subtypes of the MOR, DOR and KOR that exist in vivo that cannot be recapitulated in cell-based systems expressing a single receptor. Thus, it is extremely challenging to design better, more selective opioid drugs until the molecular nature of the pharmacological subtypes has been defined. We propose that heterodimerization of the opioid receptors could alter their pharmacology and explain the opioid subtypes. In particular, several lines of evidence suggest that DOR1 may be a heterodimer complex of MOR and DOR while DOR2 may be a homomer/monomer of DOR. Our preliminary data suggest that agonism of DOR1 reduces drinking and antagonism at DOR2 reduces drinking. Thus, our goal is to design new ligands that are agonists at DOR1 (MOR/DOR heterodimers) but antagonists at DOR2. We have designed a series of novel bivalent ligands that we predict may have these desired properties. We have designed our bivalent ligands to have novel function(s) on heterodimers that are distinct from their effects on homomers/monomers, due to their "tuned affinity". Specifically, each of our bivalent ligands features a high affinity compound tethered to a low affinity compound. We take this approach because one of the inherent drawbacks to "classical" bivalent ligands is that they are not selective for heterodimeric receptors. That is, each pharmacophore in classic bivalent ligands can interact with high affinity with its matching monomeric/homomeric receptor as well as with a receptor that is part of a heterodimer. In the two Specific Aims here, we will generate "tuned affinity" bivalent ligands and use them together with a unique set of tools, including cell lines and a complete set of opioid receptor knock out mice, to probe the functional role of the MOR/DOR heterodimers. PUBLIC HEALTH RELEVANCE: Here, we have designed several new tuned affinity bivalent opioid ligands that we believe will have novel pharmacologies due to their selective activity profile on MOR/DOR heterodimers. We will use these ligands to probe the existence and functional relevance of the MOR/DOR heterodimer.

描述（由申请人提供）：选择性靶向阿片类受体异二聚体7。项目摘要/摘要阿片类受体是治疗急性和慢性疼痛适应症的重要目标，并且是目前在治疗酒精中毒治疗的药理干预措施中的少数目标之一。阿片受体系统由三个高度相关的受体组成：MU，Delta和Kappa阿片受体（分别为MOR，DOR和KOR）。使用敲除动物的研究表明，这些受体中的每一个都对伤害感受和饮酒都有独特的贡献。尽管进行了50多年的研究，但阿片类药物受体的药理学仍然存在一些谜团。特别是，在表达单个受体的基于细胞的系统中无法概括过体内的MOR，DOR和KOR的药理学定义的亚型。因此，在定义了药理学亚型的分子性质之前，设计更好，更有选择性的阿片类药物是极具挑战性的。我们建议阿片类药物受体的异二聚化可以改变其药理学并解释阿片类药物亚型。特别是，有几条证据表明DOR1可能是MOR和DOR的异二聚体复合物，而DOR2可能是DOR的同源物/单体。我们的初步数据表明，DOR1的激动剂减少DOR2时的饮酒和拮抗作用会减少饮酒。因此，我们的目标是设计新的配体，这些配体是DOR1（MOR/DOR异二聚体）的激动剂，但在DOR2的拮抗剂。我们设计了一系列新型的二价配体，我们预测这些配体可能具有这些所需的特性。我们已经设计了二价配体，以在异二聚体上具有新功能，这些异二聚体与它们对同性恋者/单体的影响不同，因为它们的“调谐亲和力”。具体而言，我们的每个二价配体都有一个高亲和力化合物束缚在低亲和力化合物上。我们采用这种方法是因为“经典”二价配体的固有缺点之一是它们对异二聚体受体不是选择性。也就是说，经典的二价配体中的每个药效团都可以与高亲和力与其匹配的单体/同源受体以及杂质二聚体一部分的受体相互作用。在这里的两个特定目的中，我们将生成“调整的亲和力”二价配体，并将它们与一组独特的工具一起使用，包括细胞系和一组完整的阿片类药物受体敲除小鼠，以探测MOR/DOR异质二聚体的功能作用。 公共卫生相关性：在这里，我们设计了几种新调整的亲和力二价阿片体配体，我们认为由于其在MOR/DOR异质二聚体上的选择性活动概况，我们认为将具有新颖的药理学。我们将使用这些配体来探测MOR/DOR异二聚体的存在和功能相关性。