PDB 6pov citation summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI

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

Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB

J Med Chem 63 4528-4554 (2020)

Related entries: 6pmv, 6pmw, 6pmx, 6pmy, 6pmz, 6pn0, 6pn1, 6pn2, 6pn3, 6pn4, 6pn5, 6pn6, 6pn7, 6pn8, 6pn9, 6pna, 6pnb, 6pnc, 6pnd, 6pne, 6pnf, 6png, 6pnh, 6po5, 6po7, 6po8, 6po9, 6poa, 6pob, 6poc, 6pot, 6pou, 6pow, 6pox, 6poy, 6poz, 6pp0, 6pp1, 6pp2, 6pp3, 6pp4

Cited: 6 times

PMID: 32302123

10.1021/acs.jmedchem.9b01573

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.

Articles - 6pov mentioned but not cited (2)

First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 63 4528-4554 (2020)
Network Pharmacology and Experimental Validation to Explore the Mechanism of Qing-Jin-Hua-Tan-Decoction Against Acute Lung Injury. Xiao S, Liu L, Sun Z, Liu X, Xu J, Guo Z, Yin X, Liao F, Xu J, You Y, Zhang T. Front Pharmacol 13 891889 (2022)

Reviews citing this publication (1)

Neuronal Nitric Oxide Synthase and Post-Translational Modifications in the Development of Central Nervous System Diseases: Implications and Regulation. Maccallini C, Amoroso R. Molecules 28 6691 (2023)

Articles citing this publication (3)

Design, Synthesis and Pharmacological Evaluation of Novel C²,C³-Quinoxaline Derivatives as Promising Anxiolytic Agents. Maltsev DV, Skripka MO, Spasov AA, Vassiliev PM, Perfiliev MA, Divaeva LN, Zubenko AA, Morkovnik AS, Klimenko AI, Miroshnikov MV, Klochkov VG, Ianalieva LR. Int J Mol Sci 23 14401 (2022)
Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Dong J, Li D, Kang L, Luo C, Wang J. Biophys Rep 9 159-175 (2023)
Molecular Mechanics Simulations and Experimental Investigation of the Effect of Tadalafil on Various Inflammatory Pain Mediators. Domiati S, Abd El Galil K, Ragab H. ACS Omega 7 43747-43758 (2022)

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