First Contact: 7‑Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate

Inhibition of neuronal nitric oxide
synthase (nNOS), an enzyme
implicated in neurodegenerative disorders, is an attractive strategy
for treating or preventing these diseases. We previously developed
several classes of 2-aminoquinoline-based nNOS inhibitors, but these
compounds had drawbacks including off-target promiscuity, low activity
against human nNOS, and only modest selectivity for nNOS over related
enzymes. In this study, we synthesized new nNOS inhibitors based on
7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS,
human eNOS, and murine and (in some cases) human iNOS. Compounds with
a meta-relationship between the aminoquinoline and
a positively charged tail moiety were potent and had up to nearly
900-fold selectivity for human nNOS over human eNOS. X-ray crystallography
indicates that the amino groups of some compounds occupy a water-filled
pocket surrounding an nNOS-specific aspartate residue (absent in eNOS).
This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines
the first aminoquinolines to interact with this residue.