S-methyl-L-Thiocitrulline (hydrochloride)

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Background

S-methyl-L-Thiocitrulline is a potent NOS inhibitor with selectivity toward the neuronal nitric oxide synthases (nNOS) compared to eNOS (endothelial NOS) and iNOS (inducible NOS) [1, 2].
Nitric oxide synthases (NOSs) belong to a family of enzymes involved in catalyzing the production of nitric oxide (NO) from L-arginine. As an important cellular signaling molecule, NO has been implicated in modulating vascular tone, insulin secretion, airway tone, and peristalsis, angiogenesis and neural development. Until now, three isozymes of NOS have been identified: eNOS (endothelial NOS), nNOS (neuronal NOS), and iNOS (inducible NOS). The eNOS plays a critical role in embryonic heart development and morphogenesis of coronary arteries and cardiac valves. The nNOS functions as a retrograde neurotransmitter important in long term potentiation and has been involved in the development of nervous system. The iNOS produces large amounts of NO as a defense mechanism and is an important factor in the response of the body to attack by parasites, bacterial infection, and tumor growth [3].
S-methyl-L-thiocitrulline reversed hypotension in the rat model of septic peritonitis and in dogs administered endotoxin [1]. S-Methyl-L-thiocitrulline inhibited the oxidation of L-arginine and the L-arginine-independent oxidation of NADPH by nNOS from human brain. The Kd value of S-Methyl-L-thiocitrulline was 1.2 nM. L-Arginine was a competitive inhibitor of Me-TC with competition constant (Ks) value of 2.2 μM. Me-TC was a less potent inhibitor of human iNOS (Ki values of 34 nM) and human eNOS (Ki value of 11 nM) [2].

[1] Narayanan K, Spack L, McMillan K, et al. S-alkyl-L-thiocitrullines. Potent stereoselective inhibitors of nitric oxide synthase with strong pressor activity in vivo[J]. Journal of Biological Chemistry, 1995, 270(19): 11103-11110.
[2] Furfine E S, Harmon M F, Paith J E, et al. Potent and selective inhibition of human nitric oxide synthases. Selective inhibition of neuronal nitric oxide synthase by S-methyl-L-thiocitrulline and S-ethyl-L-thiocitrulline[J]. Journal of Biological Chemistry, 1994, 269(43): 26677-26683.
[3] Stuehr D J, Griffith O W. Mammalian nitric oxide synthases[J]. Advances in Enzymology and Related Areas of Molecular Biology, Volume 65, 2006: 287-346.