Novel kappa-Opioid Receptor Agonists for the Treatment of Neuroinflammation

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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.