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

Giovanni Tangherlini, Dmitrii V. Kalinin, Dirk Schepmann, Tao Che, Nadine Mykicki, Sonja Ständer, Karin Loser, Bernhard Wünsch

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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 (T H 1) and T H 17 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.

Original languageEnglish
Pages (from-to)893-907
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
DOIs
StatePublished - Jan 24 2019

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