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Chemical Compound Review

PYRAZINE     pyrazine

Synonyms: Piazine, pyrazin, Paradiazine, p-Diazine, SureCN5179, ...
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Disease relevance of pyrazine

  • Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands [1].
  • Structure-activity relationship studies indicated that alterations at the 2- and 3-positions of the pyrazine ring of 6 had a significant effect on cytotoxicity and the inhibition of mitosis in cultured lymphoid leukemia L1210 cells [2].
  • Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases [1].
  • Both sense and antisense strands of PCR-amplified mEH DNA were cloned into an M13mp19 phage vector in order to examine the nucleotide sequences of PCR-amplified mEH DNA derived from the poly(A)+ RNA isolated from thiazole- or pyrazine-treated animals [3].
  • Radiolytic and photochemical reduction of the hypoxic cytotoxin 1,2-dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide (RB90740) and a potential mechanism for hypoxia-selective toxicity [4].

Psychiatry related information on pyrazine


High impact information on pyrazine

  • Although OBP was originally isolated as a pyrazine binding protein, both rat and bovine OBP also bind the odorants [3H]methyldihydrojasmonate and 3,7-dimethyl-octan-1-ol as well as 2-isobutyl-3-[3H]methoxypyrazine [6].
  • We have purified to apparent homogeneity a soluble pyrazine odorant binding protein that constitutes approximately equal to 1% of the total soluble protein in bovine nasal epithelium [7].
  • Na+/Ca2+ exchange is inhibited in both guinea pig cardiac membrane vesicles and papillary muscles in a concentration-dependent fashion by several analogs of the pyrazine diuretic amiloride [8].
  • In the present study we examine the thermodynamics of binding of two related pyrazine-derived ligands to the major urinary protein, MUP-I, using a combination of isothermal titration calorimetry (ITC), X-ray crystallography, and NMR backbone (15)N and methyl side-chain (2)H relaxation measurements [9].
  • We provide evidence for the existence of two distinct binding sites for the amiloride molecule: one for the guanidium moiety and another for the pyrazine ring [10].

Chemical compound and disease context of pyrazine


Biological context of pyrazine


Anatomical context of pyrazine

  • Epoxide hydrolase activity toward the hydrolysis of 2-cyanoethylene oxide (CEO), the epoxide metabolite of the rat carcinogen acrylonitrile, was not significant in hepatic microsomes from untreated rats, but was substantially induced by treatment with thiazole or pyrazine [3].
  • It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity [19].
  • Sequence analysis of the pyrazine-binding protein from bovine olfactory mucosa reveals marked homology with a family of proteins of unknown function found in the urine of the adult male mouse and rat [20].
  • METHODS AND MATERIALS: A new series of experimental bioreductive durgs, fused pyrazine mono-N-oxides, was evaluated in vitro for aerobic and hypoxic cytotoxicity in the HT29 human colon adenocarcinoma cell line by using clonogenic assays [21].
  • Our results are consistent with the contention that these pyrazine derivatives not only interact with receptor protein molecules in the biological membranes, but also modulate these receptor properties via their interaction with the lipid bilayer altering the membrane microviscosity [22].

Associations of pyrazine with other chemical compounds

  • It was concluded that neither the 2-amino group nor an intact pyrazine ring of folates and folate analogs are essential for the binding of folates to the active site of mouse liver FPGS but that the pyrazine ring probably serves to position other regions of the folate molecule that interact with amino acid residues in the active site [23].
  • These kinetic data correlate well with the increases in mEH mRNA observed after administration of thiazole or pyrazine to rats [3].
  • In vitro evaluation indicated that activity was reduced by removal of the pyridine ring nitrogen of 29 to give 14 and was destroyed by increasing the basicity of the pyrazine ring of 29 to give 32 and 47 [24].
  • Furthermore, the kite conformation is more preferred in solvents with substantial hydrogen-bonding acidity: weak hydrogen-bonding interactions between the mildly basic quinoxaline and pyrazine nitrogen atoms and solvent molecules are more efficient in the open kite than in the closed vase form [25].
  • Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way [26].

Gene context of pyrazine

  • In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERalpha than on ERbeta [27].
  • M1 agonist activity was related to the length of the side chain attached to the pyrazine ring, with maximal activity being obtained with the hexyloxy side chain [28].
  • Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ETA-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2-pyrazinyl)-1- naphthalenesulfonamides (7m, ETA pIC50 8.1) [29].
  • Amiloride analogues with nonaromatic substituents on the 5-amino group or different substituents on carbon-6 of the pyrazine ring were tested as inhibitors of monoamine oxidase A and B in rat brain homogenate [30].
  • Another protein (approximately 43 kd) cross-reacting with polyclonal mEH antibody was found to be increased concomitantly following pyrazine treatment [3].

Analytical, diagnostic and therapeutic context of pyrazine

  • Long-range magnetic order in Mn[N(CN)2]2(pyz) (pyz = pyrazine). Susceptibility, magnetization, specific heat, and neutron diffraction measurements and electronic structure calculations [31].
  • The level of polymerase chain reaction (PCR)-amplified mEH DNA derived from poly(A)+ RNA was clearly elevated following either thiazole or pyrazine treatment relative to that from untreated animals [3].
  • The site of action of ICI 206,970, an aminomethylphenol pyrazine derivative, with effects on Na+ and water excretion similar to hydrochlorothazide, was determined using free-flow micropuncture and in vivo microperfusion techniques [32].
  • In this phase II trial, patients with no prior chemotherapy or immunotherapy for metastatic disease and performance status (SWOG) of 0-1, were treated with pyrazine diazohydroxide at a dose of 100 mg/m2/day by i.v. bolus injection over 5-15 minutes for 5 consecutive days every 6 weeks [33].
  • Pyrazine-induced hepatic microsomes exhibited approximately 5-fold increases in CYP2E1-catalysed metabolic activities, whereas the hepatic microsomes obtained after treatment of animals with both AS and pyrazine showed rates comparable to or less than those in control microsomes [34].


  1. Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. Ghosh, A.K., Thompson, W.J., Holloway, M.K., McKee, S.P., Duong, T.T., Lee, H.Y., Munson, P.M., Smith, A.M., Wai, J.M., Darke, P.L. J. Med. Chem. (1993) [Pubmed]
  2. Antimitotic agents. Alterations at the 2,3-positions of ethyl (5-amino-1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamates. Temple, C., Rener, G.A., Comber, R.N., Waud, W.R. J. Med. Chem. (1991) [Pubmed]
  3. Induction of rat liver microsomal epoxide hydrolase by thiazole and pyrazine: hydrolysis of 2-cyanoethylene oxide. Kim, S.G., Kedderis, G.L., Batra, R., Novak, R.F. Carcinogenesis (1993) [Pubmed]
  4. Radiolytic and photochemical reduction of the hypoxic cytotoxin 1,2-dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide (RB90740) and a potential mechanism for hypoxia-selective toxicity. Naylor, M.A., Sutton, B.M., Nolan, J., O'Neill, P., Fielden, E.M., Adams, G.E., Stratford, I.J. Int. J. Radiat. Oncol. Biol. Phys. (1994) [Pubmed]
  5. The pyrazine-binding protein and olfaction. Bignetti, E., Cattaneo, P., Cavaggioni, A., Damiani, G., Tirindelli, R. Comp. Biochem. Physiol., B (1988) [Pubmed]
  6. Odorant-binding protein: localization to nasal glands and secretions. Pevsner, J., Sklar, P.B., Snyder, S.H. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  7. Isolation and characterization of an olfactory receptor protein for odorant pyrazines. Pevsner, J., Trifiletti, R.R., Strittmatter, S.M., Snyder, S.H. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  8. Inhibition of Na+/Ca2+ exchange in membrane vesicle and papillary muscle preparations from guinea pig heart by analogs of amiloride. Siegl, P.K., Cragoe, E.J., Trumble, M.J., Kaczorowski, G.J. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  9. Thermodynamics of binding of 2-methoxy-3-isopropylpyrazine and 2-methoxy-3-isobutylpyrazine to the major urinary protein. Bingham, R.J., Findlay, J.B., Hsieh, S.Y., Kalverda, A.P., Kjellberg, A., Perazzolo, C., Phillips, S.E., Seshadri, K., Trinh, C.H., Turnbull, W.B., Bodenhausen, G., Homans, S.W. J. Am. Chem. Soc. (2004) [Pubmed]
  10. Diversity of channels generated by different combinations of epithelial sodium channel subunits. McNicholas, C.M., Canessa, C.M. J. Gen. Physiol. (1997) [Pubmed]
  11. Enhancement of biliary excretion of aflatoxin B(1) and suppression of hepatic ornithine decarboxylase activity by 2-(allylthio)pyrazine in rats. Ha, T.G., Mar, W.C., Kim, S.G., Surh, Y.J., Kim, N.D. Mutat. Res. (1999) [Pubmed]
  12. Schedule dependence, activity against natural metastases, and cross-resistance of pyrazine diazohydroxide (sodium salt, NSC 361456) in preclinical models in vivo. Harrison, S.D., Plowman, J., Dykes, D.J., Waud, W.R., Griswold, D.P. Cancer Chemother. Pharmacol. (1990) [Pubmed]
  13. Spin-gap formation and thermal structural studies in reduced hybrid layered vanadates. Yan, B., Luo, J., Dube, P., Sefat, A.S., Greedan, J.E., Maggard, P.A. Inorganic chemistry. (2006) [Pubmed]
  14. Pharmacokinetic changes of intravenous 2-(allylthio) pyrazine, a chemoprotective agent, in rats with acute renal failure induced by uranyl nitrate. Lee, E.J., Kim, E.J., Kim, Y.G., Chung, H.C., Kim, S.H., Kim, D.H., Lee, I., Kim, S.G., Lee, M.G. Res. Commun. Mol. Pathol. Pharmacol. (2002) [Pubmed]
  15. Traditional GFP-type cyclization and unexpected fragmentation site in a purple chromoprotein from Anemonia sulcata, asFP595. Zagranichny, V.E., Rudenko, N.V., Gorokhovatsky, A.Y., Zakharov, M.V., Balashova, T.A., Arseniev, A.S. Biochemistry (2004) [Pubmed]
  16. Synthesis and antiviral evaluation of certain novel pyrazinoic acid C-nucleosides. Walker, J.A., Liu, W., Wise, D.S., Drach, J.C., Townsend, L.B. J. Med. Chem. (1998) [Pubmed]
  17. Differential expression of microsomal epoxide hydrolase gene by azole heterocycles in rats. Kim, S.G., Jung, K.H., Yang, W.K., Kim, N.D. Biochem. Pharmacol. (1994) [Pubmed]
  18. Structure-activity relationship of amiloride analogs as blockers of epithelial Na channels: I. Pyrazine-ring modifications. Li, J.H., Cragoe, E.J., Lindemann, B. J. Membr. Biol. (1985) [Pubmed]
  19. Tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines: vascular smooth muscle relaxants and antihypertensive agents. Abou-Gharbia, M., Freed, M.E., McCaully, R.J., Silver, P.J., Wendt, R.L. J. Med. Chem. (1984) [Pubmed]
  20. Homology between the pyrazine-binding protein from nasal mucosa and major urinary proteins. Cavaggioni, A., Sorbi, R.T., Keen, J.N., Pappin, D.J., Findlay, J.B. FEBS Lett. (1987) [Pubmed]
  21. Fused pyrazine mono-n-oxides as bioreductive drugs. II Cytotoxicity in human cells and oncogenicity in a rodent transformation assay. Langmuir, V.K., Laderoute, K.R., Mendonca, H.L., Sutherland, R.M., Hei, T.K., Liu, S.X., Hall, E.J., Naylor, M.A., Adams, G.E. Int. J. Radiat. Oncol. Biol. Phys. (1996) [Pubmed]
  22. Pyrazine derivatives affect membrane fluidity of vascular smooth muscle microsomes in relation to their biological activity. Nie, S.Q., Kwan, C.Y., Epand, R.M. Eur. J. Pharmacol. (1993) [Pubmed]
  23. Relative substrate activities of structurally related pteridine, quinazoline, and pyrimidine analogs for mouse liver folylpolyglutamate synthetase. Moran, R.G., Colman, P.D., Jones, T.R. Mol. Pharmacol. (1989) [Pubmed]
  24. Potential antimitotic agents. Synthesis of some ethyl benzopyrazin-7-ylcarbamates, ethyl pyrido[3,4-b]pyrazin-7-ylcarbamates, and ethyl pyrido[3,4-e]-as-triazin-7-ylcarbamates. Temple, C., Rener, G.A. J. Med. Chem. (1990) [Pubmed]
  25. Conformational behavior of pyrazine-bridged and mixed-bridged cavitands: a general model for solvent effects on thermal "vase-kite" switching. Roncucci, P., Pirondini, L., Paderni, G., Massera, C., Dalcanale, E., Azov, V.A., Diederich, F. Chemistry (Weinheim an der Bergstrasse, Germany) (2006) [Pubmed]
  26. Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide. Speirs, R.J., Welch, J.T., Cynamon, M.H. Antimicrob. Agents Chemother. (1995) [Pubmed]
  27. Estrogenic diazenes: heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes. Ghosh, U., Ganessunker, D., Sattigeri, V.J., Carlson, K.E., Mortensen, D.J., Katzenellenbogen, B.S., Katzenellenbogen, J.A. Bioorg. Med. Chem. (2003) [Pubmed]
  28. Novel functional M1 selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-1,2,5,6-tetrahydro-1-methylpyridines. Construction of a molecular model for the M1 pharmacophore. Ward, J.S., Merritt, L., Klimkowski, V.J., Lamb, M.L., Mitch, C.H., Bymaster, F.P., Sawyer, B., Shannon, H.E., Olesen, P.H., Honoré, T. J. Med. Chem. (1992) [Pubmed]
  29. New non-peptide endothelin-A receptor antagonists: synthesis, biological properties, and structure-activity relationships of 5-(dimethylamino)-N-pyridyl-,-N-pyrimidinyl-,-N-pyridazinyl-, and -N-pyrazinyl-1-naphthalenesulfonamides. Bradbury, R.H., Bath, C., Butlin, R.J., Dennis, M., Heys, C., Hunt, S.J., James, R., Mortlock, A.A., Sumner, N.F., Tang, E.K., Telford, B., Whiting, E., Wilson, C. J. Med. Chem. (1997) [Pubmed]
  30. Inhibition of monoamine oxidase by analogues of amiloride. Palatý, V., Cragoe, E.J. Mol. Pharmacol. (1989) [Pubmed]
  31. Long-range magnetic order in Mn[N(CN)2]2(pyz) (pyz = pyrazine). Susceptibility, magnetization, specific heat, and neutron diffraction measurements and electronic structure calculations. Manson, J.L., Huang, Q., Lynn, J.W., Koo, H.J., Whangbo, M.H., Bateman, R., Otsuka, T., Wada, N., Argyriou, D.N., Miller, J.S. J. Am. Chem. Soc. (2001) [Pubmed]
  32. A micropuncture study on the renal site of action of ICI 206,970, a unique eukalemic diuretic. Johnston, P.A., Kau, S.T. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  33. A phase II trial of pyrazine diazohydroxide in patients with disseminated malignant melanoma and no prior chemotherapy--Southwest Oncology Group study. Whitehead, R.P., Unger, J.M., Flaherty, L.E., Kraut, E.H., Mills, G.M., Klein, C.E., Chapman, R.A., Doolittle, G.C., Hammond, N., Sondak, V.K. Investigational new drugs. (2002) [Pubmed]
  34. Inhibition of cytochrome P4502E1 expression by organosulfur compounds allylsulfide, allylmercaptan and allylmethylsulfide in rats. Kwak, M.K., Kim, S.G., Kwak, J.Y., Novak, R.F., Kim, N.D. Biochem. Pharmacol. (1994) [Pubmed]
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