REVIEW: Structure and Activity of NO Synthase Inhibitors Specific to the L-Arginine Binding Site

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S. Ya. Proskuryakov^1*, A. G. Konoplyannikov¹, V. G. Skvortsov¹, A. A. Mandrugin², and V. M. Fedoseev²

¹Medical Radiological Research Center, Russian Academy of Medical Sciences, ul. Koroleva 4, 249036 Obninsk, Russia; fax: (7-095) 956-1440; E-mail: noo@mrrc.obninsk.ru; pros@mrrc.obninsk.ru

²Faculty of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia; fax: (7-095) 939-3187; E-mail: fedoseev@radio.chem.msu.ru

^* To whom correspondence should be addressed.

Received December 26, 2003; Revision received April 12, 2004

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Synthesis of compounds containing a fragment similar to the guanidine group of L-arginine, which is a substrate of nitric oxide synthase (NOS), is the main direction in creating NOS inhibitors. The inhibitory effect of such compounds is caused not only by their competition with the substrate for the L-arginine-binding site and/or oxidizing center of the enzyme (heme) but also by interaction with peptide motifs of the enzyme that influence its dimerization, affinity for cofactors, and interaction with associated proteins. Structures, activities, and relative in vitro and in vivo specificities of various NOS inhibitors (amino acid and non-amino acid) with linear or cyclic structure and containing guanidine, amidine, or isothiuronium group are considered. These properties are mainly analyzed by comparison with effects of the inhibitors on the inducible NOS.

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KEY WORDS: nitric oxide synthase (NOS), NOS activity regulation, reactive oxygen species, substrate-like inhibitors, chemical structure, activity and selectivity of NOS inhibitors

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