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

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.