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二聚体 7. 项目摘要/摘要 阿片受体是治疗急性和慢性疼痛适应症的重要靶点，也是目前在治疗酒精中毒时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：mu、delta 和 kappa 阿片受体（分别为 MOR、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饮酒都有独特的贡献。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。特别是，体内存在药理学定义的 MOR、DOR 和 KOR 亚型，这些亚型无法在表达单一受体的基于细胞的系统中重现。因此，在药理学亚型的分子性质得到明确之前，设计更好、更具选择性的阿片类药物极具挑战性。我们认为阿片受体的异二聚化可以改变其药理学并解释阿片亚型。特别是，多个证据表明 DOR1 可能是 MOR 和 DOR 的异二聚体复合物，而 DOR2 可能是 DOR 的同聚体/单体。我们的初步数据表明，DOR1 的激动作用减少了饮酒，而 DOR2 的拮抗作用则减少了饮酒。因此，我们的目标是设计新的配体，它们是 DOR1（MOR/DOR 异二聚体）的激动剂，但是 DOR2 的拮抗剂。我们设计了一系列新型二价配体，我们预测它们可能具有这些所需的特性。我们设计的二价配体在异二聚体上具有新的功能，由于其“调整的亲和力”，这些功能不同于它们对同聚体/单体的作用。具体来说，我们的每个二价配体都具有与低亲和力化合物相连的高亲和力化合物。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/同聚受体以及作为异二聚体一部分的受体以高亲和力相互作用。在这里的两个具体目标中，我们将生成“调整亲和力”的二价配体，并将它们与一套独特的工具（包括细胞系和一整套阿片受体敲除小鼠）一起使用，以探测 MOR/ DOR 异二聚体。 公共卫生相关性：在这里，我们设计了几种新的亲和力调整的二价阿片类配体，我们相信它们将具有新颖的药理学作用，因为它们对 MOR/DOR 异二聚体具有选择性活性。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。