Novel kappa-Opioid Receptor Agonists for the Treatment of Neuroinflammation

用于治疗神经炎症的新型 kappa-阿片受体激动剂

• 批准号: 491896827
• 负责人: Professorin Dr. Karin Loser
• 金额: --
• 依托单位: Institut für Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/491896827?language=en
• 关键词: Novel; kappa; Opioid; Receptor; Agonists

It has been shown that the endogenous opioid system plays an important role in the pathogenesis of Multiple Sclerosis (MS). Activation of the kappa-opioid receptor (KOR) is mainly responsible for the beneficial effects observed after treatment of MS patients with opioids. Since KOR is expressed on both immune cells and neuronal cells, KOR agonists are able to regulate cytokine production and immune cell activation as well as to exert direct beneficial effects in the CNS by inducing remyelination. Therefore, activation of KOR could represent a novel promising approach for the treatment of neuroinflammatory and neurodegenerative disorders such as MS or EAE.In preliminary studies, we have developed quinoline- and quinoxaline-based KOR agonists with high affinity, selectivity, full agonistic activity and a slight bias for the beta-arrestin-2 pathway. These KOR agonists reduced the production of pro-inflammatory cytokines (e.g. IL-6, TNFalfa). The anti-inflammatory effect of these KOR agonists correlated with their KOR affinity. The fluoroethyltriazole derivative ameliorated the disease severity in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mouse model of MS. The observed effects were mediated via KOR signalling, since off-target effects were excluded by using KOR deficient mouse mutants.In this project, we aim at novel KOR agonists based on novel scaffolds. In particular, diverse substituents in 4- or 5-position of the perhydroquinoline system will allow versatile modifications, which are not possible with the existing KOR agonists. KOR agonists with diverse substituents will allow fine-tuning of pharmacodynamic and pharmacokinetic properties. We are particular interested in (1) biased KOR agonists activating selectively a particular pathway, (2) very polar KOR agonists, which do not trigger direct CNS effects and (3) fluorinated KOR agonists for the development of fluorinated PET tracers.The novel KOR agonists together with the already prepared KOR agonists will be used to develop a better understanding of the relevance of KOR signaling in inflammatory and degenerative CNS disorders such as MS and EAE. The effect of KOR agonists on phenotype, function and migratory activity of immune cells will be explored. A novel approach for the treatment of CNS inflammatory processes is pursued by employing very polar KOR agonists, which are not able to penetrate the blood brain barrier. The effect of KOR agonists and KOR signaling on brain endothelial cells and the integrity of the blood-brain barrier will be investigated.

研究表明，内源性阿片系统在多发性硬化（MS）的发病机制中起重要作用。κ-阿片受体（KOR）的激活主要是阿片类药物治疗MS患者后观察到的有益作用的原因。由于KOR在免疫细胞和神经元细胞上表达，因此KOR激动剂能够调节细胞因子产生和免疫细胞活化，以及通过诱导髓鞘再生在CNS中发挥直接有益作用。因此，激活KOR可能是一种新的有前途的方法，用于治疗神经炎症和神经退行性疾病，如MS或EAE.In初步研究中，我们已经开发了喹啉和喹喔啉为基础的KOR激动剂具有高亲和力，选择性，充分的激动活性和轻微的偏见β-arrestin-2途径。这些KOR激动剂减少促炎细胞因子（例如IL-6、TNFa）的产生。这些KOR激动剂的抗炎作用与它们的KOR亲和力相关。氟乙基三唑衍生物改善了髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）MS小鼠模型的疾病严重程度。所观察到的效果是通过KOR信号传导介导的，因为脱靶效应被排除使用KOR缺陷小鼠mutants.In这个项目中，我们的目标是基于新的支架的新型KOR激动剂。特别地，在全氢喹啉系统的4-或5-位上的不同取代基将允许通用的修饰，这对于现有的KOR激动剂是不可能的。具有不同取代基的KOR激动剂将允许药效学和药代动力学性质的微调。我们对（1）选择性激活特定途径的偏向性KOR激动剂特别感兴趣，（2）非常极性的KOR激动剂，不会引起直接的中枢神经系统效应;（3）新的KOR激动剂与已经制备的KOR激动剂一起将用于更好地理解KOR信号传导在炎症和退行性CNS中的相关性。例如MS和EAE。将探索KOR激动剂对免疫细胞的表型、功能和迁移活性的影响。通过使用不能穿透血脑屏障的非常极性的KOR激动剂来寻求治疗CNS炎性过程的新方法。将研究KOR激动剂和KOR信号传导对脑内皮细胞和血脑屏障完整性的影响。