Nitric oxide (NO) is an important cell signaling molecule that regulates blood pressure in endothelial cells, acts as an important molecule in macrophage cells for immune system defense against pathogens, and is a neurotransmitter in neuronal cells. Pathologically produced excesses of neuronal NO, however, have been correlated with almost all neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease. The objective of this proposal is to diminish this excess neuronal NO by inhibition of the neuronal form of the enzyme that produces it, nitric oxide synthase (NOS). The successes we have had in the design of selective neuronal nitric oxide synthase (nNOS) inhibitors during the last funding period will be the springboard for future design and synthesis efforts, using crystallographic images of our inhibitors bound to NOS and structure-based computer design of new structures. At present two of our inhibitors have been found to be very effective at preventing cerebral palsy phenotype in a rabbit model for cerebral palsy. For this indication, administration by injection is acceptable. The important next step taken will be to enhance the oral bioavailability of these compounds while increasing their potency and selectivity for nNOS over the other two isoforms of NOS, endothelial NOS (eNOS) and inducible NOS (iNOS) to minimize side effects and toxicities. One key observation made in the last funding period was an unexpected binding conformation of some of our selective inhibitors, which opens up the door for more bioavailable inhibitors. Once oral bioavailability improves, then these compounds may become first-in-class treatments for Parkinson's, Alzheimer's, and Huntington's diseases. Basic pharmacokinetic properties of the new molecules will be measured to determine their metabolic stability and ability to enter the brain. Neuroprotective studies in a Parkinson rat model will be conducted. The standard treatment for Parkinson's disease is L-dopa;however, prolonged use of this drug produces abnormal involuntary movements (AIMs) or dyskinesia. Orally bioavailable compounds will be tested for their ability to prevent dyskinesia in both rats and primates treated with L-dopa. Finally, further studies will be undertaken to elucidate the mechanism for how NOS catalyzes the oxidation of L-arginine to citrulline and NO using alternative substrates.

Public Health Relevance

Pathologically produced excesses of neuronal nitric oxide have been correlated with almost every neurodegenerative disease, including Parkinson's disease, Alzheimer's disease, and Huntington's disease. The objective of this proposal is to diminish this excess neuronal nitric oxide by synthesis and evaluation of compounds that inhibit the neuronal form of the enzyme that produces nitric oxide, namely, nitric oxide synthase. When accomplished, these compounds could be first-in-class treatments for these neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049725-19
Application #
8607552
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Fabian, Miles
Project Start
1994-04-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2014
Total Cost
$402,370
Indirect Cost
$115,675
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Li, Huiying; Evenson, Ryan J; Chreifi, Georges et al. (2018) Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides. Biochemistry 57:6319-6325
Pensa, Anthony V; Cinelli, Maris A; Li, Huiying et al. (2017) Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. J Med Chem 60:7146-7165
Cinelli, Maris A; Li, Huiying; Chreifi, Georges et al. (2017) Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. J Med Chem 60:3958-3978
Do, Ha T; Wang, Heng-Yen; Li, Huiying et al. (2017) Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. J Med Chem 60:9360-9375
Holden, Jeffrey K; Lewis, Matthew C; Cinelli, Maris A et al. (2016) Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors. Biochemistry 55:5587-5594
Wang, Heng-Yen; Qin, Yajuan; Li, Huiying et al. (2016) Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. J Med Chem 59:4913-25
Cinelli, Maris A; Li, Huiying; Pensa, Anthony V et al. (2016) Correction to Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. J Med Chem 59:1246
Li, Huiying; Wang, Heng-Yen; Kang, Soosung et al. (2016) Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase. Biochemistry 55:3702-7
Mukherjee, Paramita; Li, Huiying; Sevrioukova, Irina et al. (2015) Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase. J Med Chem 58:1067-88
Kang, Soosung; Li, Huiying; Tang, Wei et al. (2015) 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. J Med Chem 58:5548-60

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