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J Med Chem. 2019 Jan 24;62(2):893-907. doi: 10.1021/acs.jmedchem.8b01609. Epub 2019 Jan 9.

Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation.

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Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Corrensstraße 48 , D-48149 Münster , Germany.
Department of Pharmacology , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
Department of Dermatology , University of Münster , von-Esmarch-Street 58 , D-48149 Münster , Germany.
CRC1009 Breaking Barriers and CRC-TR 128 Multiple Sclerosis , University of Münster , D-48149 Münster , Germany.
Cells-in-Motion Cluster of Excellence (EXC 1003-CiM) , Westfälische Wilhelms-Universität Münster , D-48149 Münster , Germany.


Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective κ-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.

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