Neuronal Nitric Oxide Synthase Inhibitors

Sigma offers two potent peptidomimetic isoform-selective nNOS inhibitors and several related nNOS products.

Nitric oxide (NO) is a potent secondary messenger that is both highly reactive and highly diffusible [1]. It is generated physiologically by a family of enzymes, referred to as NO synthases (NOS, E.C. 1.14.13.39). These enzymes catalyze the oxidation of the L-arginine substrate to L-citrulline and nitric oxide. There are three structurally distinct isoforms of NOS: two are constitutively expressed, neuronal NOS (nNOS, NOS1) and endothelial NOS (eNOS, NOS3), while the third is an inducible form found in macrophages and microglia in the nervous system (iNOS, NOS2). The primary sequence homology is only 50% among isoforms, in contrast to the high sequence conservation observed across species.

NO as a secondary messenger has proven to be a paradox [1]. NO produced by nNOS and eNOS is indispensable in neurotransmission and the regulation of vasodilation. NO produced by iNOS is involved in defense against microbial pathogens. However, the overproduction of NO plays a key role in the pathology of a wide range of disorders including diabetes, inflammatory diseases such as septic shock and arthritis, ischemia-reperfusion injury, stroke, neuropathic pain and various chronic neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's.

Given the existence of tissue-specific NOS isoforms and the important physiological roles of NO, the development of isoform-selective NOS inhibitors as therapeutic agents has become an area of active research. Most amino acid-based inhibitors are irreversible and possess minimal selectivity. N^ω-Nitro-L-arginine (Prod. No. N5501) is a weak inhibitor of iNOS, displaying an IC₅₀ value of 8.1 µM, and though more potent at nNOS and eNOS, the selectivity is similar, displaying IC₅₀ values of 0.025 µM and 0.09 µM, respectively [2-5]. Similarly, although 7-nitroindazole (Prod. No. N7778) exhibits neuroprotective properties and has been described as a relatively selective nNOS inhibitor, it displays minimally different IC₅₀ values between nNOS and eNOS isoforms (0.71 µM and 0.8 µM, respectively) [6-10]. However, in a series of studies beginning with the screening of a library of conformationally constrained arginine analogs, Huang et al. [11] and Hah et al. [12] identified two novel nNOS inhibitors, specifically L-N^ω-Nitroarginine-2,4-L-diaminobutyric amide (L-ArgNO2-L-Dbu-NH2, Prod. No. N3411) and (4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N'-nitroguanidine (Prod. No. A5727). To date, these compounds have by far the highest selectivity for nNOS, particularly in relation to eNOS (Table 1).

In summary, L-N^ω-Nitroarginine-2,4-diaminobutyric amide are potent and highly targeted tools for the study of nNOS functions and its role in neurodegenerative diseases.

Manufactured and sold under license to US patent number 6,274,557.

NOS Related Products available from Sigma-RBI

References

1. Kerwin, J.F. Jr, et al., J. Med. Chem., 38, 4343-4362 (1995).
2. Reif, D.W. and McCreedy, S.A., Arch. Biochem. Biophys., 320, 170-176 (1995).
3. Dawson, V.L., et al., Proc. Natl. Acad. Sci. USA, 88, 6368-6371 (1991).
4. Michel, A.D., et al., Br. J. Pharmacol., 109, 287-288 (1993).
5. Modin, A., et al., Neuroscience, 62, 189 (1994).
6. Garthwaite, J., et al., Trends Neurosci., 14, 60-67 (1991).
7. Moore, P.K., et al., Br. J. Pharmacol., 108, 296-297 (1993).
8. Wolfe, D.J., et al., Arch. Biochem. Biophys., 314, 360 (1994).
9. Klatt, P., et al., J. Biol. Chem., 269, 13861-16866 (1994).
10. Schulz, J.B., et al., J. Neurochem., 64, 936-939 (1995).
11. Huang H., et al., J. Med. Chem., 43, 2938-2945 (2000).
12. Hah, J.M. et al., J. Med. Chem., 44, 2667-2670 (2001).

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