Selectively Targeting Opioid Receptor Heterodimers

说明(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指征的重要靶标，也是目前在酒精中毒治疗中少数几个接受药物干预的靶标之一。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)。利用基因敲除动物进行的研究表明，这些受体中的每一个都对伤害性感受和饮酒有独特的贡献。尽管进行了50多年的研究，但阿片受体的药理仍有几个谜团。特别是，体内存在的药物定义的MOR、DOR和KOR亚型不能在表达单一受体的细胞系统中概括。因此，在确定药理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其具有挑战性的。我们认为阿片受体的异二聚化可以改变它们的药理作用，并解释阿片亚型。特别是，有几条证据表明DOR1可能是MOR和DOR的杂二聚体复合体，而DOR2可能是DOR的同质/单体。我们的初步数据表明，DOR1的激动化减少了饮酒，而DOR2的拮抗则减少了饮酒。因此，我们的目标是设计新的配体，既是DOR1(MOR/DOR异二聚体)的激动剂，又是DOR2的拮抗剂。我们设计了一系列新的二价配体，我们预测它们可能具有这些理想的性质。我们设计了我们的二价配体对异二聚体具有新的功能(S)，由于它们的“可调谐亲和力”，不同于它们对同/单体的影响。具体地说，我们的每个二价配体都有一个高亲和力的化合物与一个低亲和力的化合物相连。我们采用这种方法是因为“经典的”二价配体的一个固有缺陷是它们对异二聚体受体不具有选择性。也就是说，经典二价配体中的每个药效团都可以与其匹配的单体/同聚体受体以及作为异二聚体一部分的受体相互作用。在这里的两个具体目标中，我们将产生调谐亲和力的二价配体，并将它们与一套独特的工具一起使用，包括细胞系和一整套阿片受体基因敲除小鼠，以探索MOR/DOR异源二聚体的功能作用。 公共卫生相关性：在这里，我们设计了几个新的调谐亲和力二价阿片配体，我们相信，由于它们对MOR/DOR异二聚体的选择性活性，它们将具有新的药理作用。我们将使用这些配体来探索MOR/DOR异二聚体的存在及其功能相关性。

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.