1. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
- Author
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Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, and Silverman RB
- Subjects
- Aminoquinolines chemical synthesis, Aminoquinolines metabolism, Aminoquinolines pharmacokinetics, Animals, Blood-Brain Barrier metabolism, Catalytic Domain, Crystallography, X-Ray, Enzyme Assays, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacokinetics, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes chemistry, Isoenzymes genetics, Isoenzymes metabolism, Microsomes, Liver metabolism, Molecular Structure, Mutagenesis, Site-Directed, Mutation, Nitric Oxide Synthase Type I chemistry, Nitric Oxide Synthase Type I genetics, Nitric Oxide Synthase Type I metabolism, Permeability, Protein Binding, Rats, Structure-Activity Relationship, Aminoquinolines pharmacology, Aspartic Acid chemistry, Enzyme Inhibitors pharmacology, Nitric Oxide Synthase Type I antagonists & inhibitors
- Abstract
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.
- Published
- 2020
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