%0 Journal Article
%T Arginine-Based Inhibitors of Nitric Oxide Synthase: Therapeutic Potential and Challenges
%A Jan V¨ªte£¿ek
%A Anton¨ªn Lojek
%A Giuseppe Valacchi
%A Luk¨¢£¿ Kubala
%J Mediators of Inflammation
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/318087
%X In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a summary of their biochemical properties as well as their observed effects both in vitro and in vivo. Furthermore, we focus in particular on their pharmacology and use in recent clinical studies. The potential of newly designed specific NOS inhibitors developed by means of modern drug development strategies is highlighted. 1. Introduction Nitric oxide (NO) is a crucial signaling molecule in vertebrates. NO is generated by NOSes. In vertebrates, three isoforms of NOS have been identified: endothelial NOS (eNOS, also referred as NOS3), neuronal NOS (nNOS, also referred as NOS1), and inducible NOS (iNOS, also referred as NOS2). The endothelial isoform is expressed constitutively in the endothelium lining of blood vessels. Neuronal NOS is constitutively expressed as well and primarily located in the central nervous system and skeletal and heart muscle cells. Inducible NOS is expressed in macrophages and some other cell types upon their activation by a wide range of proinflammatory stimuli. The activity of eNOS and nNOS is controlled by the calcium level via calmodulin-calcium interaction. Conversely iNOS has calmodulin bound permanently; this is why its function depends solely on the expression level [1, 2]. All NOSes metabolize L-arginine to L-citrulline and NO via two consecutive NADPH-dependent monooxygenations (Figure 1(a)). The active NOS consists of two identical monomers, each one having reductase and oxygenase domains. The reductase domain contains a NADPH-/NADP- binding site and a two-component (FAD, FMN) electron transport chain to deliver reducing equivalents to the
%U http://www.hindawi.com/journals/mi/2012/318087/