Nitric Oxide Synthases and Their Inhibitors: A Review

Anshika       Mittal; Rita       Kakkar
Abstract

Nitric Oxide (NO), an important biological mediator, is involved in the regulation of the cardiovascular, nervous and immune systems in mammals. Synthesis of NO is catalyzed by its biosynthetic enzyme, Nitric Oxide Synthase (NOS). There are three main isoforms of the enzyme, neuronal NOS, endothelial NOS and inducible NOS, which have very similar structures but differ in their expression and activities. NO is produced in the active site of the enzyme in two distinct cycles from oxidation of the substrate L-arg (L-arginine) in nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reaction. NOS has gained considerable attention of biochemists due to its complexity and unique catalytic mechanism. The review focuses on NOS structure, its function and catalytic reaction mechanism. In particular, the review is concluded with a discussion on the role of all three isoforms of NOS in physiological and pathological conditions and their inhibitors with a focus on the role of computational techniques in their development.
Keywords: Nitric oxide, nitric oxide synthase, selectivity, computational, arginine, inhibition, heme.
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[1] 
Messner, S.; Leitner, S.; Bommassar, C.; Golderer, G.; Gröbner, P.; Werner, E.R.; Werner-Felmayer, G. Physarum nitric oxide synthases: genomic structures and enzymology of recombinant proteins. Biochem. J.,  2009, 418(3), 691-700.
[http://dx.doi.org/10.1042/BJ20080192] [PMID:  19046139] 
[2] 
Stuehr, D.J. Mammalian nitric oxide synthases. Biochim. Biophys. Acta,  1999, 1411(2-3), 217-230.
[http://dx.doi.org/10.1016/S0005-2728(99)00016-X] [PMID:  10320659] 
[3] 
Sudhamsu, J.; Crane, B.R. Bacterial nitric oxide synthases: what are they good for? Trends Microbiol.,  2009, 17(5), 212-218.
[http://dx.doi.org/10.1016/j.tim.2009.02.003] [PMID:  19375324] 
[4] 
Zhou, L.; Zhu, D.Y. Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide,  2009, 20(4), 223-230.
[http://dx.doi.org/10.1016/j.niox.2009.03.001] [PMID:  19298861] 
[5] 
Daff, S. NO synthase: structures and mechanisms. Nitric Oxide,  2010, 23(1), 1-11.
[http://dx.doi.org/10.1016/j.niox.2010.03.001] [PMID:  20303412] 
[6] 
Luckhart, S.; Rosenberg, R. Gene structure and polymorphism of an invertebrate nitric oxide synthase gene. Gene,  1999, 232(1), 25-34.
[http://dx.doi.org/10.1016/S0378-1119(99)00121-3] [PMID:  10333518] 
[7] 
Tejero, J.; Stuehr, D. Tetrahydrobiopterin in nitric oxide synthase. IUBMB Life,  2013, 65(4), 358-365.
[http://dx.doi.org/10.1002/iub.1136] [PMID: 23441062] 
[8] 
Wang, J.; Stuehr, D.J.; Ikeda-Saito, M.; Rousseau, D.L. Heme coordination and structure of the catalytic site in nitric oxide synthase. J. Biol. Chem.,  1993, 268(30), 22255-22258.
[PMID: 7693663] 
[9] 
Feng, C. Mechanism of nitric oxide synthase regulation: electron transfer and interdomain interactions. Coord. Chem. Rev.,  2012, 256(3-4), 393-411.
[http://dx.doi.org/10.1016/j.ccr.2011.10.011] [PMID:  22523434] 
[10] 
Hoeben, A.; Landuyt, B.; Highley, M.S.; Wildiers, H.; Van Oosterom, A.T.; De Bruijn, E.A. Vascular endothelial growth factor and angiogenesis. Pharmacol. Rev.,  2004, 56(4), 549-580.
[http://dx.doi.org/10.1124/pr.56.4.3] [PMID:  15602010] 
[11] 
Liu, V.W.; Huang, P.L. Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc. Res.,  2008, 77(1), 19-29.
[PMID:  17658499] 
[12] 
Vallance, P.; Leiper, J. Blocking NO synthesis: how, where and why? Nat. Rev. Drug Discov.,  2002, 1(12), 939-950.
[http://dx.doi.org/10.1038/nrd960] [PMID:  12461516] 
[13] 
Li, H.; Poulos, T.L. Structure-function studies on nitric oxide synthases. J. Inorg. Biochem.,  2005, 99(1), 293-305.
[http://dx.doi.org/10.1016/j.jinorgbio.2004.10.016] [PMID:  15598508] 
[14] 
Rand, M.J. Nitrergic transmission: nitric oxide as a mediator of non-adrenergic, non-cholinergic neuro-effector transmission. Clin. Exp. Pharmacol. Physiol.,  1992, 19(3), 147-169.
[http://dx.doi.org/10.1111/j.1440-1681.1992.tb00433.x] [PMID:  1325878] 
[15] 
Nathan, C. Nitric oxide as a secretory product of mammalian cells. FASEB J.,  1992, 6(12), 3051-3064.
[http://dx.doi.org/10.1096/fasebj.6.12.1381691] [PMID:  1381691] 
[16] 
Kane, A.J.; Barker, J.E.; Mitchell, G.M.; Theile, D.R.; Romero, R.; Messina, A.; Wagh, M.; Fraulin, F.O.; Morrison, W.A.; Stewart, A.G. Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival. Br. J. Pharmacol.,  2001, 132(8), 1631-1638.
[http://dx.doi.org/10.1038/sj.bjp.0703944] [PMID:  11309233] 
[17] 
Nandagopal, K.; Dawson, T.M.; Dawson, V.L. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J. Pharmacol. Exp. Ther.,  2001, 297(2), 474-478.
[PMID:  11303032] 
[18] 
Ignarro, L.J. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J. Physiol. Pharmacol.,  2002, 53(4 Pt 1), 503-514.
[PMID:  12512688] 
[19] 
Crane, B.R.; Arvai, A.S.; Gachhui, R.; Wu, C.; Ghosh, D.K.; Getzoff, E.D.; Stuehr, D.J.; Tainer, J.A. The structure of nitric oxide synthase oxygenase domain and inhibitor complexes. Science,  1997, 278(5337), 425-431.
[http://dx.doi.org/10.1126/science.278.5337.425] [PMID:  9334294] 
[20] 
Crane, B.R.; Arvai, A.S.; Ghosh, D.K.; Wu, C.; Getzoff, E.D.; Stuehr, D.J.; Tainer, J.A. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science,  1998, 279(5359), 2121-2126.
[http://dx.doi.org/10.1126/science.279.5359.2121] [PMID:  9516116] 
[21] 
Li, H.; Shimizu, H.; Flinspach, M.; Jamal, J.; Yang, W.; Xian, M.; Cai, T.; Wen, E.Z.; Jia, Q.; Wang, P.G.; Poulos, T.L. The novel binding mode of N-alkyl-N'-hydroxyguanidine to neuronal nitric oxide synthase provides mechanistic insights into NO biosynthesis. Biochemistry,  2002, 41(47), 13868-13875.
[http://dx.doi.org/10.1021/bi020417c] [PMID:  12437343] 
[22] 
Raman, C.S.; Li, H.; Martásek, P.; Král, V.; Masters, B.S.; Poulos, T.L. Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell,  1998, 95(7), 939-950.
[http://dx.doi.org/10.1016/S0092-8674(00)81718-3] [PMID:  9875848] 
[23] 
Garcin, E.D.; Bruns, C.M.; Lloyd, S.J.; Hosfield, D.J.; Tiso, M.; Gachhui, R.; Stuehr, D.J.; Tainer, J.A.; Getzoff, E.D. Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase. J. Biol. Chem.,  2004, 279(36), 37918-37927.
[http://dx.doi.org/10.1074/jbc.M406204200] [PMID:  15208315] 
[24] 
Zhang, J.; Martàsek, P.; Paschke, R.; Shea, T.; Siler Masters, B.S.; Kim, J.J. Crystal structure of the FAD/NADPH-binding domain of rat neuronal nitric-oxide synthase. Comparisons with NADPH-cytochrome P450 oxidoreductase. J. Biol. Chem.,  2001, 276(40), 37506-37513.
[http://dx.doi.org/10.1074/jbc.M105503200] [PMID:  11473123] 
[25] 
Stuehr, D.J. Structure-function aspects in the nitric oxide synthases. Annu. Rev. Pharmacol. Toxicol.,  1997, 37(1), 339-359.
[http://dx.doi.org/10.1146/annurev.pharmtox.37.1.339] [PMID:  9131257] 
[26] 
Siddhanta, U.; Wu, C.; Abu-Soud, H.M.; Zhang, J.; Ghosh, D.K.; Stuehr, D.J. Heme iron reduction and catalysis by a nitric oxide synthase heterodimer containing one reductase and two oxygenase domains. J. Biol. Chem.,  1996, 271(13), 7309-7312.
[http://dx.doi.org/10.1074/jbc.271.13.7309] [PMID:  8631749] 
[27] 
Hobbs, A.J.; Higgs, A.; Moncada, S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu. Rev. Pharmacol. Toxicol.,  1999, 39(1), 191-220.
[http://dx.doi.org/10.1146/annurev.pharmtox.39.1.191] [PMID:  10331082] 
[28] 
Gachhui, R.; Abu-Soud, H.M.; Ghosha, D.K.; Presta, A.; Blazing, M.A.; Mayer, B.; George, S.E.; Stuehr, D.J. Neuronal nitric-oxide synthase interaction with calmodulin-troponin C chimeras. J. Biol. Chem.,  1998, 273(10), 5451-5454.
[http://dx.doi.org/10.1074/jbc.273.10.5451] [PMID:  9488666] 
[29] 
Konas, D.W.; Takaya, N.; Sharma, M.; Stuehr, D.J. Role of Asp1393 in catalysis, flavin reduction, NADP(H) binding, FAD thermodynamics, and regulation of the nNOS flavoprotein. Biochemistry,  2006, 45(41), 12596-12609.
[http://dx.doi.org/10.1021/bi061011t] [PMID:  17029414] 
[30] 
Konas, D.W.; Zhu, K.; Sharma, M.; Aulak, K.S.; Brudvig, G.W.; Stuehr, D.J. The FAD-shielding residue Phe1395 regulates neuronal nitric-oxide synthase catalysis by controlling NADP+ affinity and a conformational equilibrium within the flavoprotein domain. J. Biol. Chem.,  2004, 279(34), 35412-35425.
[http://dx.doi.org/10.1074/jbc.M400872200] [PMID:  15180983] 
[31] 
Panda, K.; Adak, S.; Konas, D.; Sharma, M.; Stuehr, D.J. A conserved aspartate (Asp-1393) regulates NADPH reduction of neuronal nitric-oxide synthase: implications for catalysis. J. Biol. Chem.,  2004, 279(18), 18323-18333.
[http://dx.doi.org/10.1074/jbc.M310391200] [PMID:  14966111] 
[32] 
Wang, Z.Q.; Wei, C.C.; Stuehr, D.J. A conserved tryptophan 457 modulates the kinetics and extent of N-hydroxy-L-arginine oxidation by inducible nitric-oxide synthase. J. Biol. Chem.,  2002, 277(15), 12830-12837.
[http://dx.doi.org/10.1074/jbc.M111967200] [PMID:  11823464] 
[33] 
Bastian, N.R.; Hibbs, J.B., Jr Assembly and regulation of NADPH oxidase and nitric oxide synthase. Curr. Opin. Immunol.,  1994, 6(1), 131-139.
[http://dx.doi.org/10.1016/0952-7915(94)90044-2] [PMID:  7513523] 
[34] 
Fischmann, T.O.; Hruza, A.; Niu, X.D.; Fossetta, J.D.; Lunn, C.A.; Dolphin, E.; Prongay, A.J.; Reichert, P.; Lundell, D.J.; Narula, S.K.; Weber, P.C. Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation. Nat. Struct. Biol.,  1999, 6(3), 233-242.
[http://dx.doi.org/10.1038/6675] [PMID:  10074942] 
[35] 
Stuehr, D.J. Enzymes of the L-arginine to nitric oxide pathway. J. Nutr.,  2004, 134(10)(Suppl.), 2748S-2751S.
[http://dx.doi.org/10.1093/jn/134.10.2748S] [PMID:  15465779] 
[36] 
Gachhui, R.; Ghosh, D.K.; Wu, C.; Parkinson, J.; Crane, B.R.; Stuehr, D.J. Mutagenesis of acidic residues in the oxygenase domain of inducible nitric-oxide synthase identifies a glutamate involved in arginine binding. Biochemistry,  1997, 36(17), 5097-5103.
[http://dx.doi.org/10.1021/bi970331x] [PMID:  9136868] 
[37] 
McMillan, K.; Masters, B.S. Prokaryotic expression of the heme- and flavin-binding domains of rat neuronal nitric oxide synthase as distinct polypeptides: identification of the heme-binding proximal thiolate ligand as cysteine-415. Biochemistry,  1995, 34(11), 3686-3693.
[http://dx.doi.org/10.1021/bi00011a025] [PMID:  7534476] 
[38] 
Alderton, W.K.; Cooper, C.E.; Knowles, R.G. Nitric oxide synthases: structure, function and inhibition. Biochem. J.,  2001, 357(Pt 3), 593-615.
[http://dx.doi.org/10.1042/bj3570593] [PMID:  11463332] 
[39] 
Andrew, P.J.; Mayer, B. Enzymatic function of nitric oxide synthases. Cardiovasc. Res.,  1999, 43(3), 521-531.
[http://dx.doi.org/10.1016/S0008-6363(99)00115-7] [PMID:  10690324] 
[40] 
Ghosh, S.; Wolan, D.; Adak, S.; Crane, B.R.; Kwon, N.S.; Tainer, J.A.; Getzoff, E.D.; Stuehr, D.J. Mutational analysis of the tetrahydrobiopterin-binding site in inducible nitric-oxide synthase. J. Biol. Chem.,  1999, 274(34), 24100-24112.
[http://dx.doi.org/10.1074/jbc.274.34.24100] [PMID:  10446182] 
[41] 
Sagami, I.; Sato, Y.; Daff, S.; Shimizu, T. Aromatic residues and neighboring Arg414 in the (6R)-5,6,7, 8-tetrahydro-L-biopterin binding site of full-length neuronal nitric-oxide synthase are crucial in catalysis and heme reduction with NADPH. J. Biol. Chem.,  2000, 275(34), 26150-26157.
[http://dx.doi.org/10.1074/jbc.M000534200] [PMID:  10846172] 
[42] 
Wang, Z.Q.; Wei, C.C.; Ghosh, S.; Meade, A.L.; Hemann, C.; Hille, R.; Stuehr, D.J. A conserved tryptophan in nitric oxide synthase regulates heme-dioxy reduction by tetrahydrobiopterin. Biochemistry,  2001, 40(43), 12819-12825.
[http://dx.doi.org/10.1021/bi011182s] [PMID:  11669618] 
[43] 
Kwon, N.S.; Nathan, C.F.; Stuehr, D.J. Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J. Biol. Chem.,  1989, 264(34), 20496-20501.
[PMID: 2584226] 
[44] 
Tayeh, M.A.; Marletta, M.A. Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J. Biol. Chem.,  1989, 264(33), 19654-19658.
[PMID: 2584186] 
[45] 
Baek, K.J.; Thiel, B.A.; Lucas, S.; Stuehr, D.J. Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. J. Biol. Chem.,  1993, 268(28), 21120-21129.
[PMID: 7691806] 
[46] 
Venema, R.C.; Ju, H.; Zou, R.; Ryan, J.W.; Venema, V.J. Subunit interactions of endothelial nitric-oxide synthase. Comparisons to the neuronal and inducible nitric-oxide synthase isoforms. J. Biol. Chem.,  1997, 272(2), 1276-1282.
[http://dx.doi.org/10.1074/jbc.272.2.1276] [PMID:  8995432] 
[47] 
Crane, B.R.; Arvai, A.S.; Ghosh, S.; Getzoff, E.D.; Stuehr, D.J.; Tainer, J.A. Structures of the N(omega)-hydroxy-L-arginine complex of inducible nitric oxide synthase oxygenase dimer with active and inactive pterins. Biochemistry,  2000, 39(16), 4608-4621.
[http://dx.doi.org/10.1021/bi992409a] [PMID:  10769116] 
[48] 
Gorren, A.C.; Mayer, B. Tetrahydrobiopterin in nitric oxide synthesis: A novel biological role for pteridines. Curr. Drug Metab.,  2002, 3(2), 133-157.
[http://dx.doi.org/10.2174/1389200024605154] [PMID:  12003347] 
[49] 
Hurshman, A.R.; Krebs, C.; Edmondson, D.E.; Huynh, B.H.; Marletta, M.A. Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen. Biochemistry,  1999, 38(48), 15689-15696.
[http://dx.doi.org/10.1021/bi992026c] [PMID:  10625434] 
[50] 
Klatt, P.; Schmidt, K.; Lehner, D.; Glatter, O.; Bächinger, H.P.; Mayer, B. Structural analysis of porcine brain nitric oxide synthase reveals a role for tetrahydrobiopterin and L-arginine in the formation of an SDS-resistant dimer. EMBO J.,  1995, 14(15), 3687-3695.
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb00038.x] [PMID:  7543842] 
[51] 
Assreuy, J.; Cunha, F.Q.; Liew, F.Y.; Moncada, S. Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br. J. Pharmacol.,  1993, 108(3), 833-837.
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb12886.x] [PMID:  7682140] 
[52] 
Rogers, N.E.; Ignarro, L.J. Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine. Biochem. Biophys. Res. Commun.,  1992, 189(1), 242-249.
[http://dx.doi.org/10.1016/0006-291X(92)91550-A] [PMID:  1280418] 
[53] 
Griscavage, J.M.; Fukuto, J.M.; Komori, Y.; Ignarro, L.J. Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group. Role of tetrahydrobiopterin in modulating the inhibitory action of nitric oxide. J. Biol. Chem.,  1994, 269(34), 21644-21649.
[PMID: 7520440] 
[54] 
Ignarro, L.J.; Napoli, C.; Loscalzo, J. Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ. Res.,  2002, 90(1), 21-28.
[http://dx.doi.org/10.1161/hh0102.102330] [PMID:  11786514] 
[55] 
Vallance, P.; Charles, I. Nitric oxide in sepsis: Of mice and men. Sepsis,  1998, 1(2), 93-100.
[http://dx.doi.org/10.1023/A:1009772307518] 
[56] 
van’t Hof, R.J.; Ralston, S.H. Nitric oxide and bone. Immunology,  2001, 103(3), 255-261.
[http://dx.doi.org/10.1046/j.1365-2567.2001.01261.x] [PMID:  11454054] 
[57] 
Sanders, S.P. Nitric oxide in asthma. Pathogenic, therapeutic, or diagnostic? Am. J. Respir. Cell Mol. Biol.,  1999, 21(2), 147-149.
[http://dx.doi.org/10.1165/ajrcmb.21.2.f158] [PMID:  10423393] 
[58] 
Heneka, M.T.; Wiesinger, H.; Dumitrescu-Ozimek, L.; Riederer, P.; Feinstein, D.L.; Klockgether, T. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J. Neuropathol. Exp. Neurol.,  2001, 60(9), 906-916.
[http://dx.doi.org/10.1093/jnen/60.9.906] [PMID:  11556547] 
[59] 
Knott, C.; Stern, G.; Wilkin, G.P. Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol. Cell. Neurosci.,  2000, 16(6), 724-739.
[http://dx.doi.org/10.1006/mcne.2000.0914] [PMID:  11124893] 
[60] 
Behr-Roussel, D.; Rupin, A.; Sansilvestri-Morel, P.; Fabiani, J.N.; Verbeuren, T.J. Histochemical evidence for inducible nitric oxide synthase in advanced but non-ruptured human atherosclerotic carotid arteries. Histochem. J.,  2000, 32(1), 41-51.
[http://dx.doi.org/10.1023/A:1003958312508] [PMID:  10805384] 
[61] 
Liu, J.S.; Zhao, M.L.; Brosnan, C.F.; Lee, S.C. Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am. J. Pathol.,  2001, 158(6), 2057-2066.
[http://dx.doi.org/10.1016/S0002-9440(10)64677-9] [PMID:  11395383] 
[62] 
Víteček, J.; Lojek, A.; Valacchi, G.; Kubala, L. Arginine-based inhibitors of nitric oxide synthase: therapeutic potential and challenges. Mediators Inflamm.,  2012, 2012, 318087
[http://dx.doi.org/10.1155/2012/318087] [PMID:  22988346] 
[63] 
Litzinger, E.A.; Martásek, P.; Roman, L.J.; Silverman, R.B. Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors. Bioorg. Med. Chem.,  2006, 14(9), 3185-3198.
[http://dx.doi.org/10.1016/j.bmc.2005.12.043] [PMID:  16431112] 
[64] 
Rees, D.D.; Palmer, R.M.; Schulz, R.; Hodson, H.F.; Moncada, S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br. J. Pharmacol.,  1990, 101(3), 746-752.
[http://dx.doi.org/10.1111/j.1476-5381.1990.tb14151.x] [PMID:  1706208] 
[65] 
Aisaka, K.; Gross, S.S.; Griffith, O.W.; Levi, R. NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo? Biochem. Biophys. Res. Commun.,  1989, 160(2), 881-886.
[http://dx.doi.org/10.1016/0006-291X(89)92517-5] [PMID:  2719705] 
[66] 
Feldman, P.L.; Griffith, O.W.; Hong, H.; Stuehr, D.J. Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methylarginine requires NADPH-dependent hydroxylation. J. Med. Chem.,  1993, 36(4), 491-496.
[http://dx.doi.org/10.1021/jm00056a009] [PMID:  7682617] 
[67] 
Olken, N.M.; Osawa, Y.; Marletta, M.A. Characterization of the inactivation of nitric oxide synthase by NG-methyl-L-arginine: evidence for heme loss. Biochemistry,  1994, 33(49), 14784-14791.
[http://dx.doi.org/10.1021/bi00253a017] [PMID:  7527657] 
[68] 
Grover, R.; Zaccardelli, D.; Colice, G.; Guntupalli, K.; Watson, D.; Vincent, J.L. Glaxo Wellcome International Septic Shock Study Group. An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Crit. Care Med.,  1999, 27(5), 913-922.
[http://dx.doi.org/10.1097/00003246-199905000-00025] [PMID:  10362413] 
[69] 
Watson, D.; Grover, R.; Anzueto, A.; Lorente, J.; Smithies, M.; Bellomo, R.; Guntupalli, K.; Grossman, S.; Donaldson, J.; Le Gall, J.R. Glaxo Wellcome International Septic Shock Study Group. Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit. Care Med.,  2004, 32(1), 13-20.
[http://dx.doi.org/10.1097/01.CCM.0000104209.07273.FC] [PMID:  14707555] 
[70] 
Petros, A.; Bennett, D.; Vallance, P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet,  1991, 338(8782-8783), 1557-1558.
[http://dx.doi.org/10.1016/0140-6736(91)92376-D] [PMID:  1720856] 
[71] 
Petros, A.; Lamb, G.; Leone, A.; Moncada, S.; Bennett, D.; Vallance, P. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc. Res.,  1994, 28(1), 34-39.
[http://dx.doi.org/10.1093/cvr/28.1.34] [PMID:  7509259] 
[72] 
Olken, N.M.; Marletta, M.A. NG-methyl-L-arginine functions as an alternate substrate and mechanism-based inhibitor of nitric oxide synthase. Biochemistry,  1993, 32(37), 9677-9685.
[http://dx.doi.org/10.1021/bi00088a020] [PMID:  7690590] 
[73] 
Klatt, P.; Schmidt, K.; Brunner, F.; Mayer, B. Inhibitors of brain nitric oxide synthase. Binding kinetics, metabolism, and enzyme inactivation. J. Biol. Chem.,  1994, 269(3), 1674-1680.
[PMID:  7507482] 
[74] 
Gross, S.S.; Stuehr, D.J.; Aisaka, K.; Jaffe, E.A.; Levi, R.; Griffith, O.W. Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine. Biochem. Biophys. Res. Commun.,  1990, 170(1), 96-103.
[http://dx.doi.org/10.1016/0006-291X(90)91245-N] [PMID:  2372300] 
[75] 
Kobayashi, Y.; Ikeda, K.; Shinozuka, K.; Nara, Y.; Yamori, Y.; Hattori, K. L-nitroarginine increases blood pressure in the rat. Clin. Exp. Pharmacol. Physiol.,  1991, 18(6), 397-399.
[http://dx.doi.org/10.1111/j.1440-1681.1991.tb01470.x] [PMID:  1914242] 
[76] 
Zhang, H.Q.; Fast, W.; Marletta, M.A.; Martasek, P.; Silverman, R.B. Potent and selective inhibition of neuronal nitric oxide synthase by N ω-propyl-L-arginine. J. Med. Chem.,  1997, 40(24), 3869-3870.
[http://dx.doi.org/10.1021/jm970550g] [PMID:  9397167] 
[77] 
Olken, N.M.; Marletta, M.A. NG-allyl- and NG-cyclopropyl-L-arginine: two novel inhibitors of macrophage nitric oxide synthase. J. Med. Chem.,  1992, 35(6), 1137-1144.
[http://dx.doi.org/10.1021/jm00084a020] [PMID:  1372655] 
[78] 
Fast, W.; Levsky, M.E.; Marletta, M.A.; Silverman, R.B.N. N ω-propargyl-L-arginine and N ω-hydroxy-N ω-propargyl-L-arginine are inhibitors, but not inactivators, of neuronal and macrophage nitric oxide synthases. Bioorg. Med. Chem.,  1997, 5(8), 1601-1608.
[http://dx.doi.org/10.1016/S0968-0896(97)00109-0] [PMID:  9313865] 
[79] 
Griffith, O.W.; Kilbourn, R.G. Nitric oxide synthase inhibitors: amino acids. Methods Enzymol.,  1996, 268, 375-392.
[http://dx.doi.org/10.1016/S0076-6879(96)68040-9] [PMID:  8782604] 
[80] 
Salerno, J.C.; Frey, C.; McMillan, K.; Williams, R.F.; Masters, B.S.; Griffith, O.W. Characterization by electron paramagnetic resonance of the interactions of L-arginine and L-thiocitrulline with the heme cofactor region of nitric oxide synthase. J. Biol. Chem.,  1995, 270(46), 27423-27428.
[http://dx.doi.org/10.1074/jbc.270.46.27423] [PMID:  7499198] 
[81] 
Furfine, E.S.; Harmon, M.F.; Paith, J.E.; Knowles, R.G.; Salter, M.; Kiff, R.J.; Duffy, C.; Hazelwood, R.; Oplinger, J.A.; Garvey, E.P. 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. Biol. Chem.,  1994, 269(43), 26677-26683.
[PMID: 7523410] 
[82] 
Ijuin, R.; Umezawa, N.; Nagai, S.; Higuchi, T. Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes. Bioorg. Med. Chem. Lett.,  2005, 15(11), 2881-2885.
[http://dx.doi.org/10.1016/j.bmcl.2005.03.078] [PMID:  15911272] 
[83] 
Park, J.M.; Higuchi, T.; Kikuchi, K.; Urano, Y.; Hori, H.; Nishino, T.; Aoki, J.; Inoue, K.; Nagano, T. Selective inhibition of human inducible nitric oxide synthase by S-alkyl-L-isothiocitrulline-containing dipeptides. Br. J. Pharmacol.,  2001, 132(8), 1876-1882.
[http://dx.doi.org/10.1038/sj.bjp.0704023] [PMID:  11309260] 
[84] 
McCall, T.B.; Feelisch, M.; Palmer, R.M.; Moncada, S. Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells. Br. J. Pharmacol.,  1991, 102(1), 234-238.
[http://dx.doi.org/10.1111/j.1476-5381.1991.tb12159.x] [PMID:  1710525] 
[85] 
Babu, B.R.; Griffith, O.W. N5-(1-Imino-3-butenyl)-L-ornithine. A neuronal isoform selective mechanism-based inactivator of nitric oxide synthase. J. Biol. Chem.,  1998, 273(15), 8882-8889.
[http://dx.doi.org/10.1074/jbc.273.15.8882] [PMID:  9535869] 
[86] 
Moore, W.M.; Webber, R.K.; Jerome, G.M.; Tjoeng, F.S.; Misko, T.P.; Currie, M.G. L-N6-(1-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J. Med. Chem.,  1994, 37(23), 3886-3888.
[http://dx.doi.org/10.1021/jm00049a007] [PMID:  7525961] 
[87] 
Tang, W.; Li, H.; Poulos, T.L.; Silverman, R.B. Mechanistic studies of inactivation of inducible nitric oxide synthase by amidines. Biochemistry,  2015, 54(15), 2530-2538.
[http://dx.doi.org/10.1021/acs.biochem.5b00135] [PMID:  25811913] 
[88] 
Garvey, E.P.; Oplinger, J.A.; Furfine, E.S.; Kiff, R.J.; Laszlo, F.; Whittle, B.J.R.; Knowles, R.G. 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo. J. Biol. Chem.,  1997, 272(8), 4959-4963.
[http://dx.doi.org/10.1074/jbc.272.8.4959] [PMID:  9030556] 
[89] 
Sumayao, R., Jr; Newsholme, P.; McMorrow, T. Inducible nitric oxide synthase inhibitor 1400W increases Na+, K+ -ATPase levels and activity and ameliorates mitochondrial dysfunction in Ctns null kidney proximal tubular epithelial cells. Clin. Exp. Pharmacol. Physiol.,  2018, 45(11), 1149-1160.
[http://dx.doi.org/10.1111/1440-1681.12998] [PMID:  29924417] 
[90] 
Maccallini, C.; Patruno, A.; Besker, N.; Alì, J.I.; Ammazzalorso, A.; De Filippis, B.; Franceschelli, S.; Giampietro, L.; Pesce, M.; Reale, M.; Tricca, M.L.; Re, N.; Felaco, M.; Amoroso, R. Synthesis, biological evaluation, and docking studies of N-substituted acetamidines as selective inhibitors of inducible nitric oxide synthase. J. Med. Chem.,  2009, 52(5), 1481-1485.
[http://dx.doi.org/10.1021/jm800846u] [PMID:  19203270] 
[91] 
Maccallini, C.; Patruno, A.; Lannutti, F.; Ammazzalorso, A.; De Filippis, B.; Fantacuzzi, M.; Franceschelli, S.; Giampietro, L.; Masella, S.; Felaco, M.; Re, N.; Amoroso, R. N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase. Bioorg. Med. Chem. Lett.,  2010, 20(22), 6495-6499.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.059] [PMID:  20933416] 
[92] 
Fantacuzzi, M.; Maccallini, C.; Lannutti, F.; Patruno, A.; Masella, S.; Pesce, M.; Speranza, L.; Ammazzalorso, A.; De Filippis, B.; Giampietro, L.; Re, N.; Amoroso, R. Selective inhibition of iNOS by benzyl- and dibenzyl derivatives of N-(3-aminobenzyl)acetamidine. ChemMedChem,  2011, 6(7), 1203-1206.
[http://dx.doi.org/10.1002/cmdc.201100125] [PMID:  21567968] 
[93] 
Maccallini, C.; Montagnani, M.; Paciotti, R.; Ammazzalorso, A.; De Filippis, B.; Di Matteo, M.; Di Silvestre, S.; Fantacuzzi, M.; Giampietro, L.; Potenza, M.A.; Re, N.; Pandolfi, A.; Amoroso, R. Selective acetamidine-based nitric oxide synthase inhibitors: synthesis, docking, and biological studies. ACS Med. Chem. Lett.,  2015, 6(6), 635-640.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00149] [PMID:  26101565] 
[94] 
Maccallini, C.; Di Matteo, M.; Gallorini, M.; Montagnani, M.; Graziani, V.; Ammazzalorso, A.; Amoia, P.; De Filippis, B.; Di Silvestre, S.; Fantacuzzi, M.; Giampietro, L.; Potenza, M.A.; Re, N.; Pandolfi, A.; Cataldi, A.; Amoroso, R. Discovery of N-3-[(ethanimidoylamino)methyl]benzyl-l-prolinamide dihydrochloride: A new potent and selective inhibitor of the inducible nitric oxide synthase as a promising agent for the therapy of malignant glioma. Eur. J. Med. Chem.,  2018, 152, 53-64.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.027] [PMID:  29689474] 
[95] 
Hagen, T.J.; Bergmanis, A.A.; Kramer, S.W.; Fok, K.F.; Schmelzer, A.E.; Pitzele, B.S.; Swenton, L.; Jerome, G.M.; Kornmeier, C.M.; Moore, W.M.; Branson, L.F.; Connor, J.R.; Manning, P.T.; Currie, M.G.; Hallinan, E.A. 2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase. J. Med. Chem.,  1998, 41(19), 3675-3683.
[http://dx.doi.org/10.1021/jm970840x] [PMID:  9733492] 
[96] 
Hansen, D.W., Jr; Peterson, K.B.; Trivedi, M.; Kramer, S.W.; Webber, R.K.; Tjoeng, F.S.; Moore, W.M.; Jerome, G.M.; Kornmeier, C.M.; Manning, P.T.; Connor, J.R.; Misko, T.P.; Currie, M.G.; Pitzele, B.S. 2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide synthase (iNOS). J. Med. Chem.,  1998, 41(9), 1361-1366.
[http://dx.doi.org/10.1021/jm9704715] [PMID:  9554868] 
[97] 
Moore, W.M.; Webber, R.K.; Fok, K.F.; Jerome, G.M.; Connor, J.R.; Manning, P.T.; Wyatt, P.S.; Misko, T.P.; Tjoeng, F.S.; Currie, M.G. 2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms. J. Med. Chem.,  1996, 39(3), 669-672.
[http://dx.doi.org/10.1021/jm950766n] [PMID:  8576908] 
[98] 
Webber, R.K.; Metz, S.; Moore, W.M.; Connor, J.R.; Currie, M.G.; Fok, K.F.; Hagen, T.J.; Hansen, D.W., Jr; Jerome, G.M.; Manning, P.T.; Pitzele, B.S.; Toth, M.V.; Trivedi, M.; Zupec, M.E.; Tjoeng, F.S. Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms. J. Med. Chem.,  1998, 41(1), 96-101.
[http://dx.doi.org/10.1021/jm9705059] [PMID:  9438025] 
[99] 
Kawanaka, Y.; Kobayashi, K.; Kusuda, S.; Tatsumi, T.; Murota, M.; Nishiyama, T.; Hisaichi, K.; Fujii, A.; Hirai, K.; Naka, M.; Komeno, M.; Nakai, H.; Toda, M. Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropyridin-2-imines. Bioorg. Med. Chem. Lett.,  2002, 12(17), 2291-2294.
[http://dx.doi.org/10.1016/S0960-894X(02)00455-9] [PMID:  12161118] 
[100] 
Kawanaka, Y.; Kobayashi, K.; Kusuda, S.; Tatsumi, T.; Murota, M.; Nishiyama, T.; Hisaichi, K.; Fujii, A.; Hirai, K.; Naka, M.; Komeno, M.; Nakai, H.; Toda, M. Design and synthesis of inhibitors of inducible nitric oxide synthase. Discovery of a new chemical lead with potential for oral bioavailability. Eur. J. Med. Chem.,  2003, 38(3), 277-288.
[http://dx.doi.org/10.1016/S0223-5234(03)00017-5] [PMID:  12667694] 
[101] 
Naka, M.; Nanbu, T.; Kobayashi, K.; Kamanaka, Y.; Komeno, M.; Yanase, R.; Fukutomi, T.; Fujimura, S.; Seo, H.G.; Fujiwara, N.; Ohuchida, S.; Suzuki, K.; Kondo, K.; Taniguchi, N. A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative. Biochem. Biophys. Res. Commun.,  2000, 270(2), 663-667.
[http://dx.doi.org/10.1006/bbrc.2000.2474] [PMID:  10753680] 
[102] 
Beaton, H.; Hamley, P.; Nicholls, D.J.; Tinker, A.C.; Wallace, A.V. 3,4-Dihydro-1-isoquinolinamines: a novel class of nitric oxide synthase inhibitors with a range of isoform selectivity and potency. Bioorg. Med. Chem. Lett.,  2001, 11(8), 1023-1026.
[http://dx.doi.org/10.1016/S0960-894X(01)00119-6] [PMID:  11327580] 
[103] 
Beaton, H.; Boughton-Smith, N.; Hamley, P.; Ghelani, A.; Nicholls, D.J.; Tinker, A.C.; Wallace, A.V. Thienopyridines: nitric oxide synthase inhibitors with potent in vivo activity. Bioorg. Med. Chem. Lett.,  2001, 11(8), 1027-1030.
[http://dx.doi.org/10.1016/S0960-894X(01)00120-2] [PMID:  11327581] 
[104] 
Tinker, A.C.; Beaton, H.G.; Boughton-Smith, N.; Cook, T.R.; Cooper, S.L.; Fraser-Rae, L.; Hallam, K.; Hamley, P.; McInally, T.; Nicholls, D.J.; Pimm, A.D.; Wallace, A.V. 1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo. J. Med. Chem.,  2003, 46(6), 913-916.
[http://dx.doi.org/10.1021/jm0255926] [PMID:  12620067] 
[105] 
Faraci, W.S.; Nagel, A.A.; Verdries, K.A.; Vincent, L.A.; Xu, H.; Nichols, L.E.; Labasi, J.M.; Salter, E.D.; Pettipher, E.R. 2-Amino-4-methylpyridine as a potent inhibitor of inducible NO synthase activity in vitro and in vivo. Br. J. Pharmacol.,  1996, 119(6), 1101-1108.
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb16010.x] [PMID:  8937711] 
[106] 
Southan, G.J.; Salzman, A.L.; Szabó, C. 2-Aminopyridines: Novel inhibitors of nitric oxide synthases with potent pressure effects. Pharmacol. Commun.,  1996, 7(4), 275-286.
[107] 
Hagmann, W.K.; Caldwell, C.G.; Chen, P.; Durette, P.L.; Esser, C.K.; Lanza, T.J.; Kopka, I.E.; Guthikonda, R.; Shah, S.K.; MacCoss, M.; Chabin, R.M.; Fletcher, D.; Grant, S.K.; Green, B.G.; Humes, J.L.; Kelly, T.M.; Luell, S.; Meurer, R.; Moore, V.; Pacholok, S.G.; Pavia, T.; Williams, H.R.; Wong, K.K. Substituted 2-aminopyridines as inhibitors of nitric oxide synthases. Bioorg. Med. Chem. Lett.,  2000, 10(17), 1975-1978.
[http://dx.doi.org/10.1016/S0960-894X(00)00389-9] [PMID:  10987430] 
[108] 
Lowe, J.A., III; Qian, W.; Drozda, S.E.; Volkmann, R.A.; Nason, D.; Nelson, R.B.; Nolan, C.; Liston, D.; Ward, K.; Faraci, S.; Verdries, K.; Seymour, P.; Majchrzak, M.; Villalobos, A.; White, W.F. Structure-activity relationships of potent, selective inhibitors of neuronal nitric oxide synthase based on the 6-phenyl-2-aminopyridine structure. J. Med. Chem.,  2004, 47(6), 1575-1586.
[http://dx.doi.org/10.1021/jm030519g] [PMID:  14998342] 
[109] 
Garcin, E.D.; Arvai, A.S.; Rosenfeld, R.J.; Kroeger, M.D.; Crane, B.R.; Andersson, G.; Andrews, G.; Hamley, P.J.; Mallinder, P.R.; Nicholls, D.J.; St-Gallay, S.A.; Tinker, A.C.; Gensmantel, N.P.; Mete, A.; Cheshire, D.R.; Connolly, S.; Stuehr, D.J.; Aberg, A.; Wallace, A.V.; Tainer, J.A.; Getzoff, E.D. Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Nat. Chem. Biol.,  2008, 4(11), 700-707.
[http://dx.doi.org/10.1038/nchembio.115] [PMID:  18849972] 
[110] 
Kumar, V.; Gupta, S.P.A.A. A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors. Indian J. Biochem. Biophys.,  2013, 50(1), 72-79.
[PMID: 23617077] 
[111] 
Sharma, M.C.; Sharma, S. Investigation on quantitative structure activity relationships of a series of inducible nitric oxide. Interdiscip. Sci.,  2016, 8(4), 346-351.
[http://dx.doi.org/10.1007/s12539-016-0176-5] [PMID:  27272764] 
[112] 
Sharma, M.C. Comparative pharmacophore modeling and QSAR studies for structural requirements of some substituted 2-aminopyridines derivatives as inhibitors nitric oxide synthases. Interdiscip. Sci.,  2015, 7(2), 100-112.
[http://dx.doi.org/10.1007/s12539-015-0004-3] [PMID:  26202943] 
[113] 
Huang, H.; Martásek, P.; Roman, L.J.; Masters, B.S.; Silverman, R.B. N(ω)-Nitroarginine-containing dipeptide amides. Potent and highly selective inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  1999, 42(16), 3147-3153.
[http://dx.doi.org/10.1021/jm990111c] [PMID:  10447959] 
[114] 
Gómez-Vidal, J.A.; Martásek, P.; Roman, L.J.; Silverman, R.B. Potent and selective conformationally restricted neuronal nitric oxide synthase inhibitors. J. Med. Chem.,  2004, 47(3), 703-710.
[http://dx.doi.org/10.1021/jm030297m] [PMID:  14736250] 
[115] 
Hah, J.M.; Martásek, P.; Roman, L.J.; Silverman, R.B. Aromatic reduced amide bond peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  2003, 46(9), 1661-1669.
[http://dx.doi.org/10.1021/jm0202932] [PMID:  12699384] 
[116] 
Hah, J-M.; Roman, L.J.; Martásek, P.; Silverman, R.B. Reduced amide bond peptidomimetics. (4S)-N-(4-amino-5-[aminoakyl]aminopentyl)-N′-nitroguanidines, potent and highly selective inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  2001, 44(16), 2667-2670.
[http://dx.doi.org/10.1021/jm0101491] [PMID:  11472219] 
[117] 
Flinspach, M.L.; Li, H.; Jamal, J.; Yang, W.; Huang, H.; Hah, J-M.; Gómez-Vidal, J.A.; Litzinger, E.A.; Silverman, R.B.; Poulos, T.L. Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase. Nat. Struct. Mol. Biol.,  2004, 11(1), 54-59.
[http://dx.doi.org/10.1038/nsmb704] [PMID:  14718923] 
[118] 
Ji, H.; Li, H.; Flinspach, M.; Poulos, T.L.; Silverman, R.B. Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors. J. Med. Chem.,  2003, 46(26), 5700-5711.
[http://dx.doi.org/10.1021/jm030301u] [PMID:  14667223] 
[119] 
Ji, H.; Stanton, B.Z.; Igarashi, J.; Li, H.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors. J. Am. Chem. Soc.,  2008, 130(12), 3900-3914.
[http://dx.doi.org/10.1021/ja0772041] [PMID:  18321097] 
[120] 
Goodford, P.J. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem.,  1985, 28(7), 849-857.
[http://dx.doi.org/10.1021/jm00145a002] [PMID:  3892003] 
[121] 
Miranker, A.; Karplus, M. Functionality maps of binding sites: a multiple copy simultaneous search method. Proteins,  1991, 11(1), 29-34.
[http://dx.doi.org/10.1002/prot.340110104] [PMID:  1961699] 
[122] 
Lawton, G.R.; Ralay Ranaivo, H.; Chico, L.K.; Ji, H.; Xue, F.; Martásek, P.; Roman, L.J.; Watterson, D.M.; Silverman, R.B. Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability. Bioorg. Med. Chem.,  2009, 17(6), 2371-2380.
[http://dx.doi.org/10.1016/j.bmc.2009.02.017] [PMID:  19268602] 
[123] 
Huang, H.; Ji, H.; Li, H.; Jing, Q.; Labby, K.J.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Selective monocationic inhibitors of neuronal nitric oxide synthase. Binding mode insights from molecular dynamics simulations. J. Am. Chem. Soc.,  2012, 134(28), 11559-11572.
[http://dx.doi.org/10.1021/ja302269r] [PMID:  22731813] 
[124] 
Li, H.; Xue, F.; Kraus, J.M., II; Ji, H.; Labby, K.J.; Mataka, J.; Delker, S.L.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. Bioorg. Med. Chem.,  2013, 21(5), 1333-1343.
[http://dx.doi.org/10.1016/j.bmc.2012.12.019] [PMID:  23352768] 
[125] 
Xue, F.; Li, H.; Delker, S.L.; Fang, J.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. J. Am. Chem. Soc.,  2010, 132(40), 14229-14238.
[http://dx.doi.org/10.1021/ja106175q] [PMID:  20843082] 
[126] 
Oliveira, B.L.; Moreira, I.S.; Fernandes, P.A.; Ramos, M.J.; Santos, I.; Correia, J.D.G. Insights into the structural determinants for selective inhibition of nitric oxide synthase isoforms. J. Mol. Model.,  2013, 19(4), 1537-1551.
[http://dx.doi.org/10.1007/s00894-012-1677-8] [PMID:  23263357] 
[127] 
Xue, F.; Fang, J.; Delker, S.L.; Li, H.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  2011, 54(7), 2039-2048.
[http://dx.doi.org/10.1021/jm101071n] [PMID:  21410186] 
[128] 
Huang, H.; Li, H.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  2013, 56(7), 3024-3032.
[http://dx.doi.org/10.1021/jm4000984] [PMID:  23451760] 
[129] 
Jing, Q.; Li, H.; Chreifi, G.; Roman, L.J.; Martásek, P.; Poulos, T.L.; Silverman, R.B. Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors. Bioorg. Med. Chem. Lett.,  2013, 23(20), 5674-5679.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.034] [PMID:  23993333] 
[130] 
Jing, Q.; Li, H.; Roman, L.J.; Martásek, P.; Poulos, T.L.; Silverman, R.B. Accessible chiral linker to enhance potency and selectivity of neuronal nitric oxide synthase inhibitors. ACS Med. Chem. Lett.,  2014, 5(1), 56-60.
[http://dx.doi.org/10.1021/ml400381s] [PMID:  24660051] 
[131] 
Kang, S.; Tang, W.; Li, H.; Chreifi, G.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity. J. Med. Chem.,  2014, 57(10), 4382-4396.
[http://dx.doi.org/10.1021/jm5004182] [PMID:  24758147] 
[132] 
Young, R.J.; Beams, R.M.; Carter, K.; Clark, H.A.; Coe, D.M.; Chambers, C.L.; Davies, P.I.; Dawson, J.; Drysdale, M.J.; Franzman, K.W.; French, C.; Hodgson, S.T.; Hodson, H.F.; Kleanthous, S.; Rider, P.; Sanders, D.; Sawyer, D.A.; Scott, K.J.; Shearer, B.G.; Stocker, R.; Smith, S.; Tackley, M.C.; Knowles, R.G. Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg. Med. Chem. Lett.,  2000, 10(6), 597-600.
[http://dx.doi.org/10.1016/S0960-894X(00)00055-X] [PMID:  10741561] 
[133] 
Alderton, W.K.; Angell, A.D.; Craig, C.; Dawson, J.; Garvey, E.; Moncada, S.; Monkhouse, J.; Rees, D.; Russell, L.J.; Russell, R.J.; Schwartz, S.; Waslidge, N.; Knowles, R.G. GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. Br. J. Pharmacol.,  2005, 145(3), 301-312.
[http://dx.doi.org/10.1038/sj.bjp.0706168] [PMID:  15778742] 
[134] 
Evans, S.M.; Whittle, B.J. Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs. Eur. J. Pharmacol.,  2001, 429(1-3), 287-296.
[http://dx.doi.org/10.1016/S0014-2999(01)01327-9] [PMID:  11698048] 
[135] 
Dugo, L.; Marzocco, S.; Mazzon, E.; Di Paola, R.; Genovese, T.; Caputi, A.P.; Cuzzocrea, S. Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation. Br. J. Pharmacol.,  2004, 141(6), 979-987.
[http://dx.doi.org/10.1038/sj.bjp.0705683] [PMID:  14769784] 
[136] 
Corbett, J.A.; Tilton, R.G.; Chang, K.; Hasan, K.S.; Ido, Y.; Wang, J.L.; Sweetland, M.A.; Lancaster, J.R., Jr; Williamson, J.R.; McDaniel, M.L. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes,  1992, 41(4), 552-556.
[http://dx.doi.org/10.2337/diab.41.4.552] [PMID:  1376704] 
[137] 
Sil, S.; Ghosh, T.; Ghosh, R.; Gupta, P. Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats. J. Neuroimmunol.,  2017, 303, 51-61.
[http://dx.doi.org/10.1016/j.jneuroim.2016.12.007] [PMID:  28065581] 
[138] 
Ou, P.; Wolff, S.P. Aminoguanidine: a drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem. Pharmacol.,  1993, 46(7), 1139-1144.
[http://dx.doi.org/10.1016/0006-2952(93)90461-5] [PMID:  8216363] 
[139] 
Southan, G.J.; Zingarelli, B.; O’Connor, M.; Salzman, A.L.; Szabó, C. Spontaneous rearrangement of aminoalkylisothioureas into mercaptoalkylguanidines, a novel class of nitric oxide synthase inhibitors with selectivity towards the inducible isoform. Br. J. Pharmacol.,  1996, 117(4), 619-632.
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb15236.x] [PMID:  8646406] 
[140] 
Garvey, E.P.; Oplinger, J.A.; Tanoury, G.J.; Sherman, P.A.; Fowler, M.; Marshall, S.; Harmon, M.F.; Paith, J.E.; Furfine, E.S. Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J. Biol. Chem.,  1994, 269(43), 26669-26676.
[PMID:  7523409] 
[141] 
Southan, G.J.; Szabó, C.; Thiemermann, C. Isothioureas: Potent
inhibitors of nitric oxide synthases with variable isoform selectivity. Br. J. Pharmacol,  1995, 114(2), 510-516.
[http://dx.doi.org/10.1111/j.1476-5381.1995.tb13256.x] [PMID: 7533622] 
[142] 
Stratman, N.C.; Fici, G.J.; Sethy, V.H. U-19451A: a selective inducible nitric oxide synthase inhibitor. Life Sci.,  1996, 59(11), 945-951.
[http://dx.doi.org/10.1016/0024-3205(96)00393-1] [PMID:  8795706] 
[143] 
Raman, C.S.; Li, H.; Martásek, P.; Babu, B.R.; Griffith, O.W.; Masters, B.S.; Poulos, T.L. Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase. J. Biol. Chem.,  2001, 276(28), 26486-26491.
[http://dx.doi.org/10.1074/jbc.M102255200] [PMID:  11331290] 
[144] 
Chayah, M.; Carrión, M.D.; Gallo, M.A.; Jiménez, R.; Duarte, J.; Camacho, M.E. Development of urea and thiourea kynurenamine derivatives: synthesis, molecular modeling, and biological evaluation as nitric oxide synthase inhibitors. ChemMedChem,  2015, 10(5), 874-882.
[http://dx.doi.org/10.1002/cmdc.201500007] [PMID:  25801086] 
[145] 
Xu, G.; Chen, Y.; Shen, K.; Wang, X.; Li, F.; He, Y. The discovery of potentially selective human neuronal nitric oxide synthase (nNOS) Inhibitors: a combination of pharmacophore modelling, CoMFA, virtual screening and molecular docking studies. Int. J. Mol. Sci.,  2014, 15(5), 8553-8569.
[http://dx.doi.org/10.3390/ijms15058553] [PMID:  24830557] 
[146] 
Rosenfeld, R.J.; Garcin, E.D.; Panda, K.; Andersson, G.; Åberg, A.; Wallace, A.V.; Morris, G.M.; Olson, A.J.; Stuehr, D.J.; Tainer, J.A.; Getzoff, E.D. Conformational changes in nitric oxide synthases induced by chlorzoxazone and nitroindazoles: crystallographic and computational analyses of inhibitor potency. Biochemistry,  2002, 41(47), 13915-13925.
[http://dx.doi.org/10.1021/bi026313j] [PMID:  12437348] 
[147] 
Cheshire, D.R.; Åberg, A.; Andersson, G.M.; Andrews, G.; Beaton, H.G.; Birkinshaw, T.N.; Boughton-Smith, N.; Connolly, S.; Cook, T.R.; Cooper, A.; Cooper, S.L.; Cox, D.; Dixon, J.; Gensmantel, N.; Hamley, P.J.; Harrison, R.; Hartopp, P.; Käck, H.; Leeson, P.D.; Luker, T.; Mete, A.; Millichip, I.; Nicholls, D.J.; Pimm, A.D.; St-Gallay, S.A.; Wallace, A.V. The discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS). Bioorg. Med. Chem. Lett.,  2011, 21(8), 2468-2471.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.061] [PMID:  21398123] 
[148] 
Cottyn, B.; Acher, F.; Ramassamy, B.; Alvey, L.; Lepoivre, M.; Frapart, Y.; Stuehr, D.; Mansuy, D.; Boucher, J.L.; Vichard, D. Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile. Bioorg. Med. Chem.,  2008, 16(11), 5962-5973.
[http://dx.doi.org/10.1016/j.bmc.2008.04.056] [PMID:  18502134] 
[149] 
Le Bourdonnec, B.; Leister, L.K.; Ajello, C.A.; Cassel, J.A.; Seida, P.R.; O’Hare, H.; Gu, M.; Chu, G.H.; Tuthill, P.A.; DeHaven, R.N.; Dolle, R.E. Discovery of a series of aminopiperidines as novel iNOS inhibitors. Bioorg. Med. Chem. Lett.,  2008, 18(1), 336-343.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.073] [PMID:  18024030] 
[150] 
McMillan, K.; Adler, M.; Auld, D.S.; Baldwin, J.J.; Blasko, E.; Browne, L.J.; Chelsky, D.; Davey, D.; Dolle, R.E.; Eagen, K.A.; Erickson, S.; Feldman, R.I.; Glaser, C.B.; Mallari, C.; Morrissey, M.M.; Ohlmeyer, M.H.; Pan, G.; Parkinson, J.F.; Phillips, G.B.; Polokoff, M.A.; Sigal, N.H.; Vergona, R.; Whitlow, M.; Young, T.A.; Devlin, J.J. Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc. Natl. Acad. Sci. USA,  2000, 97(4), 1506-1511.
[http://dx.doi.org/10.1073/pnas.97.4.1506] [PMID:  10677491] 
[151] 
Martell, J.D.; Li, H.; Doukov, T.; Martásek, P.; Roman, L.J.; Soltis, M.; Poulos, T.L.; Silverman, R.B. Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency. J. Am. Chem. Soc.,  2010, 132(2), 798-806.
[http://dx.doi.org/10.1021/ja908544f] [PMID:  20014790] 
[152] 
Blasko, E.; Glaser, C.B.; Devlin, J.J.; Xia, W.; Feldman, R.I.; Polokoff, M.A.; Phillips, G.B.; Whitlow, M.; Auld, D.S.; McMillan, K.; Ghosh, S.; Stuehr, D.J.; Parkinson, J.F. Mechanistic studies with potent and selective inducible nitric-oxide synthase dimerization inhibitors. J. Biol. Chem.,  2002, 277(1), 295-302.
[http://dx.doi.org/10.1074/jbc.M105691200] [PMID:  11689556] 
[153] 
Wolff, D.J.; Datto, G.A.; Samatovicz, R.A.; Tempsick, R.A. Calmodulin-dependent nitric-oxide synthase. Mechanism of inhibition by imidazole and phenylimidazoles. J. Biol. Chem.,  1993, 268(13), 9425-9429.
[PMID: 7683651] 
[154] 
Rogerson, T.D.; Wilkinson, C.F.; Hetarski, K. Steric factors in the inhibitory interaction of imidazoles with microsomal enzymes. Biochem. Pharmacol.,  1977, 26(11), 1039-1042.
[http://dx.doi.org/10.1016/0006-2952(77)90241-6] [PMID:  880256] 
[155] 
Lee, Y.; Martásek, P.; Roman, L.J.; Masters, B.S.S.; Silverman, R.B. Imidazole-containing amino acids as selective inhibitors of nitric oxide synthases. Bioorg. Med. Chem.,  1999, 7(9), 1941-1951.
[http://dx.doi.org/10.1016/S0968-0896(99)00117-0] [PMID:  10530943] 
[156] 
Mukherjee, P.; Li, H.; Sevrioukova, I.; Chreifi, G.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  2015, 58(3), 1067-1088.
[http://dx.doi.org/10.1021/jm501719e] [PMID:  25489882] 
[157] 
Bonnefous, C.; Payne, J.E.; Roppe, J.; Zhuang, H.; Chen, X.; Symons, K.T.; Nguyen, P.M.; Sablad, M.; Rozenkrants, N.; Zhang, Y.; Wang, L.; Severance, D.; Walsh, J.P.; Yazdani, N.; Shiau, A.K.; Noble, S.A.; Rix, P.; Rao, T.S.; Hassig, C.A.; Smith, N.D. Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models. J. Med. Chem.,  2009, 52(9), 3047-3062.
[http://dx.doi.org/10.1021/jm900173b] [PMID:  19374401] 
[158] 
Payne, J.E.; Bonnefous, C.; Symons, K.T.; Nguyen, P.M.; Sablad, M.; Rozenkrants, N.; Zhang, Y.; Wang, L.; Yazdani, N.; Shiau, A.K.; Noble, S.A.; Rix, P.; Rao, T.S.; Hassig, C.A.; Smith, N.D. Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) part 2: identification of a novel, potent, and selective series of benzimidazole-quinolinone iNOS/nNOS dimerization inhibitors that are orally active in pain models. J. Med. Chem.,  2010, 53(21), 7739-7755.
[http://dx.doi.org/10.1021/jm100828n] [PMID:  20931971] 
[159] 
Zhang, H.; Zan, J.; Yu, G.; Jiang, M.; Liu, P. A combination of 3D-QSAR, molecular docking and molecular dynamics simulation studies of benzimidazole-quinolinone derivatives as iNOS inhibitors. Int. J. Mol. Sci.,  2012, 13(9), 11210-11227.
[http://dx.doi.org/10.3390/ijms130911210] [PMID:  23109848] 
[160] 
Babbedge, R.C.; Bland-Ward, P.A.; Hart, S.L.; Moore, P.K. Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br. J. Pharmacol.,  1993, 110(1), 225-228.
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb13796.x] [PMID:  7693279] 
[161] 
Mayer, B.; Klatt, P.; Werner, E.R.; Schmidt, K. Molecular mechanisms of inhibition of porcine brain nitric oxide synthase by the antinociceptive drug 7-nitro-indazole. Neuropharmacology,  1994, 33(11), 1253-1259.
[http://dx.doi.org/10.1016/0028-3908(94)90024-8] [PMID:  7532811] 
[162] 
Barp, C.G.; Mendes, C.; Lemos-Senna, E.; Assreuy, J. 7-nitroindazol-loaded nanoemulsions: Preparation, characterization and its improved inhibitory effect on nitric oxide synthase-1. Nitric Oxide,  2018, 76, 129-135.
[http://dx.doi.org/10.1016/j.niox.2017.09.003 PMID: 28943472] 
[163] 
Bland-Ward, P.A.; Moore, P.K. 7-Nitro indazole derivatives are potent inhibitors of brain, endothelium and inducible isoforms of nitric oxide synthase. Life Sci.,  1995, 57(11), PL131-PL135.
[http://dx.doi.org/10.1016/0024-3205(95)02046-L] [PMID:  7544863] 
[164] 
Handy, R.L.C.; Moore, P.K. Mechanism of the inhibition of neuronal nitric oxide synthase by 1-(2-trifluoromethylphenyl) imidazole (TRIM). Life Sci.,  1997, 60(25), PL389-PL394.
[http://dx.doi.org/10.1016/S0024-3205(97)00295-6 PMID: 9194695] 
[165] 
Sorrenti, V. Inhibition of neuronal nitric oxide synthase by Nphenacyl
imidazoles. nitric oxide,  2001, 5(1), 32-38.
[166] 
Werner, E.R.; Pitters, E.; Schmidt, K.; Wachter, H.; Werner-Felmayer, G.; Mayer, B. Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase. Biochem. J.,  1996, 320(Pt 1), 193-196.
[http://dx.doi.org/10.1042/bj3200193] [PMID:  8947486] 
[167] 
Bömmel, H.M.; Reif, A.; Fröhlich, L.G.; Frey, A.; Hofmann, H.; Marecak, D.M.; Groehn, V.; Kotsonis, P.; La, M.; Köster, S.; Meinecke, M.; Bernhardt, M.; Weeger, M.; Ghisla, S.; Prestwich, G.D.; Pfleiderer, W.; Schmidt, H.H.W. Anti-pterins as tools to characterize the function of tetrahydrobiopterin in NO synthase. J. Biol. Chem.,  1998, 273(50), 33142-33149.
[http://dx.doi.org/10.1074/jbc.273.50.33142] [PMID:  9837881] 
[168] 
Fröhlich, L.G.; Kotsonis, P.; Traub, H.; Taghavi-Moghadam, S.; Al-Masoudi, N.; Hofmann, H.; Strobel, H.; Matter, H.; Pfleiderer, W.; Schmidt, H.H. Inhibition of neuronal nitric oxide synthase by 4-amino pteridine derivatives: structure-activity relationship of antagonists of (6R)-5,6,7,8-tetrahydrobiopterin cofactor. J. Med. Chem.,  1999, 42(20), 4108-4121.
[http://dx.doi.org/10.1021/jm981129a] [PMID:  10514281] 
[169] 
Matter, H.; Kotsonis, P.; Klingler, O.; Strobel, H.; Fröhlich, L.G.; Frey, A.; Pfleiderer, W.; Schmidt, H.H.H.W. Structural requirements for inhibition of the neuronal nitric oxide synthase (NOS-I): 3D-QSAR analysis of 4-oxo- and 4-amino-pteridine-based inhibitors. J. Med. Chem.,  2002, 45(14), 2923-2941.
[http://dx.doi.org/10.1021/jm020074g] [PMID:  12086480] 
[170] 
Matter, H.; Kumar, H.S.A.; Fedorov, R.; Frey, A.; Kotsonis, P.; Hartmann, E.; Fröhlich, L.G.; Reif, A.; Pfleiderer, W.; Scheurer, P.; Ghosh, D.K.; Schlichting, I.; Schmidt, H.H.H.W. Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. J. Med. Chem.,  2005, 48(15), 4783-4792.
[http://dx.doi.org/10.1021/jm050007x] [PMID:  16033258] 
[171] 
Smith, B.C.; Underbakke, E.S.; Kulp, D.W.; Schief, W.R.; Marletta, M.A. Nitric oxide synthase domain interfaces regulate electron transfer and calmodulin activation. Proc. Natl. Acad. Sci. USA,  2013, 110(38), E3577-E3586.
[http://dx.doi.org/10.1073/pnas.1313331110] [PMID:  24003111] 
[172] 
Ohashi, K.; Yamazaki, T.; Kitamura, S.; Ohta, S.; Izumi, S.; Kominami, S. Allosteric inhibition of rat neuronal nitric-oxide synthase caused by interference with the binding of calmodulin to the enzyme. Biochim. Biophys. Acta,  2007, 1770(2), 231-240.
[http://dx.doi.org/10.1016/j.bbagen.2006.10.002] [PMID:  17098364] 
[173] 
Renodon, A.; Boucher, J.L.; Sari, M.A.; Delaforge, M.; Ouazzani, J.; Mansuy, D. Strong inhibition of neuronal nitric oxide synthase by the calmodulin antagonist and anti-estrogen drug tamoxifen. Biochem. Pharmacol.,  1997, 54(10), 1109-1114.
[http://dx.doi.org/10.1016/S0006-2952(97)00316-X] [PMID:  9464453] 
[174] 
Fukunaga, K.; Ohmitsu, M.; Miyamoto, E.; Sato, T.; Sugimura, M.; Uchida, T.; Shirasaki, Y. Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)- 1-piperazinyl]ethyl]-5, 6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ. Biochem. Pharmacol.,  2000, 60(5), 693-699.
[http://dx.doi.org/10.1016/S0006-2952(00)00370-1] [PMID:  10927028] 
[175] 
Spratt, D.E.; Israel, O.K.; Taiakina, V.; Guillemette, J.G. Regulation of mammalian nitric oxide synthases by electrostatic interactions in the linker region of calmodulin. Biochim. Biophys. Acta,  2008, 1784(12), 2065-2070.
[http://dx.doi.org/10.1016/j.bbapap.2008.09.002] [PMID:  18845278] 
[176] 
Kitamura, Y.; Arima, T.; Imaizumi, R.; Sato, T.; Nomura, Y. Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist. Eur. J. Pharmacol.,  1995, 289(2), 299-304.
[http://dx.doi.org/10.1016/0922-4106(95)90107-8] [PMID:  7542607] 
[177] 
Palacios, M.; Padron, J.; Glaria, L.; Rojas, A.; Delgado, R.; Knowles, R.; Moncada, S. Chlorpromazine inhibits both the constitutive nitric oxide synthase and the induction of nitric oxide synthase after LPS challenge. Biochem. Biophys. Res. Commun.,  1993, 196(1), 280-286.
[http://dx.doi.org/10.1006/bbrc.1993.2246] [PMID:  7692850] 
[178] 
Chen, P.F.; Wu, K.K. Two synthetic peptides corresponding to the proximal heme-binding domain and CD1 domain of human endothelial nitric-oxide synthase inhibit the oxygenase activity by interacting with CaM. Arch. Biochem. Biophys.,  2009, 486(2), 132-140.
[http://dx.doi.org/10.1016/j.abb.2009.03.015] [PMID:  19358819] 
[179] 
Wolff, D.J.; Gribin, B.J. Interferon-γ-inducible murine macrophage nitric oxide synthase: studies on the mechanism of inhibition by imidazole agents. Arch. Biochem. Biophys.,  1994, 311(2), 293-299.
[http://dx.doi.org/10.1006/abbi.1994.1240] [PMID:  7515612] 
[180] 
Wolff, D.J.; Datto, G.A.; Samatovicz, R.A. The dual mode of inhibition of calmodulin-dependent nitric-oxide synthase by antifungal imidazole agents. J. Biol. Chem.,  1993, 268(13), 9430-9436.
[PMID: 7683652] 
[181] 
Reiter, R.J.; Melchiorri, D.; Sewerynek, E.; Poeggeler, B.; Barlow-Walden, L.; Chuang, J.; Ortiz, G.G.; Acuña-Castroviejo, D. A review of the evidence supporting melatonin’s role as an antioxidant. J. Pineal Res.,  1995, 18(1), 1-11.
[http://dx.doi.org/10.1111/j.1600-079X.1995.tb00133.x] [PMID:  7776173] 
[182] 
Pozo, D.; Reiter, R.J.; Calvo, J.R.; Guerrero, J.M. Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci.,  1994, 55(24), PL455-PL460.
[http://dx.doi.org/10.1016/0024-3205(94)00532-X] [PMID:  7527477] 
[183] 
León, J.; Vives, F.; Crespo, E.; Camacho, E.; Espinosa, A.; Gallo, M.A.; Escames, G.; Acuña-Castroviejo, D. Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives. J. Neuroendocrinol.,  1998, 10(4), 297-302.
[http://dx.doi.org/10.1046/j.1365-2826.1998.00203.x] [PMID:  9630400] 
[184] 
Camacho, M.E.; León, J.; Entrena, A.; Velasco, G.; Carrión, M.D.; Escames, G.; Vivó, A.; Acuña-Castroviejo, D.; Gallo, M.A.; Espinosa, A. 4,5-dihydro-1H-pyrazole derivatives with inhibitory nNOS activity in rat brain: synthesis and structure-activity relationships. J. Med. Chem.,  2004, 47(23), 5641-5650.
[http://dx.doi.org/10.1021/jm0407714] [PMID:  15509163] 
[185] 
Fukunaga, K.; Han, F.; Shioda, N.; Moriguchi, S.; Kasahara, J.; Shirasaki, Y. DY-9760e, a novel calmodulin inhibitor, exhibits cardioprotective effects in the ischemic heart. Cardiovasc. Drug Rev.,  2006, 24(2), 88-100.
[http://dx.doi.org/10.1111/j.1527-3466.2006.00088.x] [PMID:  16961723] 
[186] 
Cinelli, M.A.; Li, H.; Chreifi, G.; Martásek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B. Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition. J. Med. Chem.,  2014, 57(4), 1513-1530.
[http://dx.doi.org/10.1021/jm401838x] [PMID:  24472039] 
[187] 
Cinelli, M.A.; Li, H.; Pensa, A.V.; Kang, S.; Roman, L.J.; Martásek, P.; Poulos, T.L.; Silverman, R.B. Phenyl ether- and aniline containing 2-aminoquinolines as potent and selective inhibitors of neuronal nitric oxide synthase. J. Med. Chem.,  2015, 58(21), 8694-8712.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01330] [PMID:  26469213] 
[188] 
Cinelli, M.A.; Li, H.; Chreifi, G.; Poulos, T.L.; Silverman, R.B. Nitrile in the hole: Discovery of a small auxiliary pocket in neuronal nitric oxide synthase leading to the development of potent and selective 2-aminoquinoline inhibitors. J. Med. Chem.,  2017, 60(9), 3958-3978.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00259] [PMID:  28422508] 
[189] 
Pensa, A.V.; Cinelli, M.A.; Li, H.; Chreifi, G.; Mukherjee, P.; Roman, L.J.; Martásek, P.; Poulos, T.L.; Silverman, R.B. Hydrophilic, potent, and selective 7-substituted 2-aminoquinolines as improved human neuronal nitric oxide synthase inhibitors. J. Med. Chem.,  2017, 60(16), 7146-7165.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00835] [PMID:  28776992] 
[190] 
Mukherjee, P.; Cinelli, M.A.; Kang, S.; Silverman, R.B. Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain. Chem. Soc. Rev.,  2014, 43(19), 6814-6838.
[http://dx.doi.org/10.1039/C3CS60467E] [PMID:  24549364] 
[191] 
Reif, D.W.; McCarthy, D.J.; Cregan, E.; Macdonald, J.E. Discovery and development of neuronal nitric oxide synthase inhibitors. Free Radic. Biol. Med.,  2000, 28(10), 1470-1477.
[http://dx.doi.org/10.1016/S0891-5849(00)00250-1] [PMID:  10927171] 
[192] 
Annedi, S.C.; Maddaford, S.P.; Ramnauth, J.; Renton, P.; Rybak, T.; Silverman, S.; Rakhit, S.; Mladenova, G.; Dove, P.; Andrews, J.S.; Zhang, D.; Porreca, F. Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine. Eur. J. Med. Chem.,  2012, 55, 94-107.
[http://dx.doi.org/10.1016/j.ejmech.2012.07.006] [PMID:  22840695] 
[193] 
Li, H.; Evenson, R.J.; Chreifi, G.; Silverman, R.B.; Poulos, T.L. Structural basis for isoform selective nitric oxide synthase inhibition by thiophene-2-carboximidamides. Biochemistry,  2018, 57(44), 6319-6325.
[http://dx.doi.org/10.1021/acs.biochem.8b00895] [PMID:  30335983] 
[194] 
Nash, K.M.; Schiefer, I.T.; Shah, Z.A. Development of a reactive oxygen species-sensitive nitric oxide synthase inhibitor for the treatment of ischemic stroke. Free Radic. Biol. Med.,  2018, 115, 395-404.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.027] [PMID:  29275014] 
[195] 
Tumer, T.B.; Onder, F.C.; Ipek, H.; Gungor, T.; Savranoglu, S.; Tok, T.T.; Celik, A.; Ay, M. Biological evaluation and molecular docking studies of nitro benzamide derivatives with respect to in vitro anti-inflammatory activity. Int. Immunopharmacol.,  2017, 43, 129-139.
[http://dx.doi.org/10.1016/j.intimp.2016.12.009] [PMID:  27988460] 
[196] 
Arias, F.; Camacho, M.E.; Carrión, M.D.; Chayah, M.; Romero, M.; Duarte, J.; Gallo, M.A. Thiadiazoline- and pyrazoline-based carboxamides and carbothioamides: Synthesis and inhibition against nitric oxide synthase. J. Chem.,  2018, 2018, 9242616
[http://dx.doi.org/10.1155/2018/9242616] 
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DOI https://dx.doi.org/10.2174/1570180816666190222154457	Print ISSN 1570-1808
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Letters in Drug Design & Discovery

Nitric Oxide Synthases and Their Inhibitors: A Review

Abstract

Graphical Abstract

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