一酸化窒素合成阻害剤/NO合成阻害剤
Nitric oxide (•NO), a highly reactive, diffusible, and unstable radical, plays an important role in the regulation of a wide range of physiological processes, including cellular immunity, angiogenesis, neurotransmission, and platelet aggregation. •NO is synthesized from L-arginine by the action of nitric oxide synthase (NOS) in a two-step oxidation process. Free •NO is a transient species with a half-life of only about five seconds. Hence, most studies on •NO action are based on the activity of NOS. •NO can diffuse across the cell membrane and react with a variety of targets. Reaction of •NO with O2 in aqueous solutions produces the relatively unreactive nitrate and nitrite ions as products. However, •NO can rapidly react with superoxide to produce highly reactive peroxynitrite (ONOO-). Almost all biological effects of •NO are achieved either directly or through other reactive nitrogen intermediates.
NOS is known to exist in three isoforms: (a) a soluble constitutively expressed enzyme found in high concentrations in the brain (bNOS, nNOS, or NOS-1), (b) a constitutively expressed endothelial membrane bound enzyme (eNOS or NOS-3), and (c) an inducible enzyme (iNOS or NOS-2) that is associated with the cytotoxic function of macrophages. These enzymes exist as homodimers, each monomer consisting of two major domains: an N-terminal oxygenase domain and a C-terminal reductase domain. The interdomain linker contains the calmodulin-binding sequence. These three isoforms exhibit similarities in their structure and mechanism of action. Calmodulin is required for the activity of all three isoforms. The activation of the constitutively expressed isoforms requires Ca2+-dependent binding of calmodulin to the enzyme. However, in the case of iNOS, calmodulin is irreversibly bound to the enzyme and its activity is regulated by its rate of synthesis rather than by Ca2+ concentration. In the absence of calmodulin iNOS is highly unstable. For their catalytic activities NOS isoforms require three distinct domains: (a) a reductase domain, (b) a calmodulin-binding domain, and (c) an oxygenase domain. The reductase domain contains the FAD and FMN moieties. The oxygenase domain, which contains the binding sites for heme, tetrahydrobiopterin, and arginine, catalyzes the conversion of L-arginine to citrulline and •NO. The maximal rate of •NO synthesis is established by the intrinsic maximum ability of the reductase domain to deliver electrons to the heme domain.
Because of the involvement of all the three NOS isozymes in various aspects of signal transduction, NOS inhibitors have gained prominence in the management of ischemic reperfusion injury, hypotensive effects of drugs, and inflammatory response to cytokines.
References:
Achike, F.I., and Kwan, C.Y. 2003. Clin. Exp. Pharmacol. Physiol. 30, 605.
Chu, C.J., et al. 2000. Clin. Sci. 99, 475.
Mori. M., and Gotoh, T. 2000. Biochem. Biophys. Res. Commun. 275, 715.
Wang, Y. et al. 1999. Crit. Rev. Neurobiol. 13, 21.
Stuehr, D.J. 1999. Biochim. Biophys. Acta 1411, 217.
Moncada, S. 1999. J. R. Soc. Med. 92, 164.
Michel, T. 1999. Braz. J. Med. Biol. Res. 32, 1361.
Jaffrey, S.R., and Snyder, S.H. 1996. Science 274, 774.
Biological Activities of Selected Nitric Oxide Synthase Inhibitors (IC50 values in μM)
| Product | Cat. No. |
eNOS
|
iNOS
|
bNOS
|
|---|---|---|---|---|
| 1400W |
50*
|
0.007*
|
2*
|
|
| Aminoguanidine, Hemisulfate | 526 | 250 | ||
| 1-Amino-2-hydroxyguanidine, p-Toluensulfate | 68 | |||
| Dexamethasone | 0.005 | |||
| NG,NG-Dimethyl-L-arginine, Dihydrochloride | ||||
| NG,NG’-Dimethyl-L-arginine, Dihydrochloride | ||||
| Diphenyleneiodonium Chloride | 0.18 | 0.05 | ||
| 2-Ethyl-2-thiopseudourea, HBr |
0.036†
|
0.017†
|
0.029†
|
|
| Haloperidol |
31†
|
|||
| L-N5-(1-Iminoethyl)ornithine, 2HCl | 0.5 | 2.2 | 3.9 | |
| MEG, Hydrochloride | ||||
| S-Methylisothiourea Sulfate (SMT) | 2.0* | |||
| S-Methyl-L-thiocitruline, Dihydrochloride | 472804 | 5.4 | 34 | 0.2 |
| NG-Monoethyl-L-arginine, Monoacetate Salt | 81 | |||
| NG-Monomethyl-D-arginine, Monoacetate Salt | -- | -- | -- | |
| NG-Monomethyl-L-arginine, Monoacetate (L-NMMA) | 0.7 | 3.9 | 0.65 | |
| L-NIL, 2HCl | -- | 3.3 | 92 | |
| NG-Nitro-L-arginine (L-NNA) | 483120 |
0.09†
|
8.1†
|
0.025†
|
| 7-Nitroindazole | 0.8 | 20 | 0.71 | |
| 7-Nitroindazole, Sodium Salt | ||||
| 7-Nitroindazole, 3-Bromo-, Sodium Salt | ||||
| nNOS Inhibitor I |
314†
|
39†
|
0.12†
|
|
| L-Thiocitrulline, 2HCl | -- |
3.6†
|
0.06†
|
|
| NG-Propyl-L-argini | 8.5 | 180 | 0.057 | |
| SKF-525A, Hydrochloride | 90 |
Key: bNOS = brain nitric oxide synthase; eNOS = endothelial nitric oxide synthase; iNOS = inducible nitric oxide synthase. Note: *: Kd; †: Ki; †: EC50
