Nitric oxide synthase (NOS) is a family of homodimeric enzymes that catalyzes the oxidation of L-arginine to L-citrulline and nitric oxide (NO). The constitutive endothelial isozyme (eNOS) produces NO involved in the regulation of smooth muscle relaxation and blood pressure and in the inhibition of platelet aggregation. A second constitutive isozyme, neuronal NOS (nNOS), makes NO that is important for neurotransmission. A third isozyme, inducible NOS (iNOS), is located in activated macrophage cells and acts as a cytotoxic agent in normal immune responses.NO overproduction by nNOS has been associated with neurodegenerative diseases, such as Parkinson's, Huntington's, and Alzheimer's diseases, stroke, and cerebral palsy. Compounds that inhibit nNOS decrease the production of NO in the brain. However, because of the importance of NO to physiological functioning, potent as well as nNOS-selective inhibitors are essential. This lecture describes the design of potent and highly dual-selective nNOS inhibitors and their modification for enhanced potency, selectivity, and lipophilicity.

Selective inhibitors of neuronal nitric oxide synthase

245th National Meeting (2013)

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