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
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Davydov, Roman; Labby, Kristin Jansen; Chobot, Sarah E et al. (2014) Enzymatic and cryoreduction EPR studies of the hydroxylation of methylated N(?)-hydroxy-L-arginine analogues by nitric oxide synthase from Geobacillus stearothermophilus. Biochemistry 53:6511-9
Li, Huiying; Jamal, Joumana; Plaza, Carla et al. (2014) Structures of human constitutive nitric oxide synthases. Acta Crystallogr D Biol Crystallogr 70:2667-74
Jing, Qing; Li, Huiying; Roman, Linda J et al. (2014) Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase. Bioorg Med Chem Lett 24:4504-10
Cinelli, Maris A; Li, Huiying; Chreifi, Georges et al. (2014) Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition. J Med Chem 57:1513-30
Li, Huiying; Jamal, Joumana; Delker, Silvia et al. (2014) The mobility of a conserved tyrosine residue controls isoform-dependent enzyme-inhibitor interactions in nitric oxide synthases. Biochemistry 53:5272-9
Jing, Qing; Li, Huiying; Roman, Linda J et al. (2014) An Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors. ACS Med Chem Lett 5:56-60
Huang, He; Li, Huiying; Yang, Sun et al. (2014) Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma. J Med Chem 57:686-700
Drury, Paul P; Davidson, Joanne O; Mathai, Sam et al. (2014) nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep. Neuropharmacology 83:62-70

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