Selectively Targeting Opioid Receptor Heterodimers

选择性靶向阿片受体异二聚体

• 批准号: 8133623
• 负责人: Pamela Michael England
• 金额: $ 22.39万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133623
• 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; 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）：选择性靶向阿片受体异源二聚体7。阿片受体是治疗急性和慢性疼痛适应症的重要靶点，也是目前在酒精中毒治疗中接受药物干预的少数靶点之一。阿片受体系统由三种高度相关的受体组成：μ、δ和κ阿片受体（分别为莫尔、DOR和KOR）。使用基因敲除动物的研究表明，这些受体中的每一种对伤害感受和酒精消耗都有独特的贡献。尽管经过50多年的研究，阿片受体的药理学仍然存在一些谜团。特别地，存在体内存在的莫尔、DOR和KOR的药理学定义的亚型，其不能在表达单一受体的基于细胞的系统中重现。因此，在确定药理学亚型的分子性质之前，设计更好、更具选择性的阿片类药物是极具挑战性的。我们认为阿片受体的异源二聚化可以改变其药理学并解释阿片亚型。特别是，若干证据表明DOR 1可能是莫尔和DOR的异二聚体复合物，而DOR 2可能是DOR的同聚体/单体。我们的初步数据表明，DOR 1的激动作用减少了饮酒，DOR 2的拮抗作用减少了饮酒。因此，我们的目标是设计新的配体，其在DOR 1处是激动剂（莫尔/DOR异二聚体），但在DOR 2处是拮抗剂。我们已经设计了一系列新的二价配体，我们预测可能具有这些所需的性质。我们已经设计了我们的二价配体，以在异二聚体上具有新的功能，这与它们对同聚体/单体的作用不同，这是由于它们的“调节亲和力”。具体而言，我们的每个二价配体的特征在于高亲和力化合物与低亲和力化合物的结合。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没有选择性。也就是说，经典二价配体中的每个药效团可以与其匹配的单体/同聚体受体以及作为异二聚体的一部分的受体以高亲和力相互作用。在这里的两个特定目标中，我们将产生“调节亲和力”的二价配体，并将它们与一组独特的工具一起使用，包括细胞系和一整套阿片受体敲除小鼠，以探测莫尔/DOR异二聚体的功能作用。 公共卫生关系：在这里，我们已经设计了几个新的调整亲和二价阿片类配体，我们相信将有新的药理学，由于其对莫尔/DOR异二聚体的选择性活性。我们将使用这些配体来探测莫尔/DOR异二聚体的存在和功能相关性。