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Chemical Compound Review

Antepan     piperazine

Synonyms: Pipersol, Antiren, Entacyl, Eraverm, Lumbrical, ...
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Disease relevance of piperazine

  • The first reported case of piperazine toxicity resembling viral hepatitis is described in a 25-year-old woman [1].
  • The evidence favors a hypersensitivity mechanism rather than a direct toxic effect of piperazine or its metabolites on the liver [1].
  • The 2.65-A resolution structure of the complex between HIV-1 RT and the bis(heteroaryl)piperazine (BHAP) NNI, 1-(5-methanesulfonamido-1H-indol-2-yl-carbonyl)-4- [3-(1-methyl-ethylamino) pyridinyl] piperazine (U-90152), reveals the inhibitor conformation and bound water molecules [2].
  • Furthermore, iron and protein deficiency reduced the efficacy of the anthelmintics pyrantel and piperazine but not levamisole [3].
  • Piperazine administration decreased the prevalence of ascariasis to 33.8% at the end of the study but growth remained unaltered [4].

Psychiatry related information on piperazine

  • Six antagonists with high affinity for 5-HT1C receptors; mianserin, (+) mianserin, 1-naphthyl piperazine, ICI 169 369, pizotifen and LY 53857 all increased the time spent in active social interaction by pairs of weight-matched rats under high light unfamiliar conditions [5].
  • The ability of piperazine agonists to reduce locomotor activity in rats was altered by long-term changes in 5-HT neurotransmission [6].
  • Our previous studies demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various rodent models of amnesia, through activation of the somatostatin neuronal system [7].
  • MB243 (a 1,3-disubstituted piperazine) is a new, potent, and selective melanocortin receptor subtype-4 agonist with potential application in the treatment of obesity and/or erectile dysfunction [8].
  • Individual differences in multiple-bag spindles of cat superficial lumbrical muscles [9].

High impact information on piperazine


Chemical compound and disease context of piperazine


Biological context of piperazine

  • We have now found that treatment of bag cell neurons with the protein kinase inhibitor 1-[5-isoquinolinesulfonyl]-2-methyl piperazine (H-7) inhibits the phorbol ester-induced enhancement of bag cell action potentials and prevents the enhancement of calcium current by phorbol esters [20].
  • Inhibition of human neutrophil chemotaxis by the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine [21].
  • The ligand binds in the minor groove at the sequence 5'-AATTC with the bulky piperazine group extending over the CxG base pair [22].
  • Other neurotransmitter uptake inhibitors, as well as cis-flupenthixol, a potent inhibitor of [3H]GBR-12935 binding to piperazine binding sites, failed to inhibit specific binding at concentrations of less than or equal to 10 microM [23].
  • The antagonists 4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-iodobenzamidoethyl] piperazine, (-)-(S)-pindolol, and spiperone also stimulated up-regulation of receptor expression [24].

Anatomical context of piperazine

  • Formation of primary and secondary myotubes in rat lumbrical muscles [25].
  • The generation and development of muscle cells in the IVth hindlimb lumbrical muscle of the rat was studied following total or partial denervation [26].
  • One of the two peripheral nerves which innervate rat lumbrical muscle was stimulated chronically in vivo during the postnatal period of synapse elimination to determine whether the differential stimulation would affect the outcome of the elimination process [27].
  • The distribution of secondary myotubes and undifferentiated mononucleated cells (presumed to be myoblasts) within foetal IVth lumbrical muscles of the rat was analyzed with serial section electron microscopy [28].
  • Embryos injected with beta-bungarotoxin (beta-BTX) on E12 or E13 suffered a partial loss of motoneurones, resulting in a reduced number of axons in the L4 ventral root (the IVth lumbrical muscle is supplied by axons in L4, L5 and L6 ventral roots) and reduced numbers of nerve terminals in the intrinsic muscles of the hindfoot [26].

Associations of piperazine with other chemical compounds

  • The selective 5-HT agonists--8-hydroxy-2-(di-n-propylamino)-tetralin, 1-(m-chlorophenyl) piperazine, and 1-(2-methoxyphenyl) piperazine--did not activate this outward current response [29].
  • Two different muscles (the fourth lumbrical and flexor digitorum quinti brevis) were only partially paralysed, since they received their innervation from the lateral plantar nerve and, in addition, from the sural nerve which was not blocked [30].
  • Predictive pharmacophore models were developed for a large series of piperidine- and piperazine-based CCR5 antagonists as anti-HIV-1 agents reported by Schering-Plough Research Institute in recent years [31].
  • The TPA-induced augmentation of apoptosis was inhibited by the protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride (H-7) [32].
  • The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity [33].

Gene context of piperazine


Analytical, diagnostic and therapeutic context of piperazine


  1. Piperazine hepatitis. Hamlyn, A.N., Morris, J.S., Sarkany, I., Sherlock, S. Gastroenterology (1976) [Pubmed]
  2. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Esnouf, R.M., Ren, J., Hopkins, A.L., Ross, C.K., Jones, E.Y., Stammers, D.K., Stuart, D.I. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  3. Nippostrongylus brasiliensis infection in the rat: effect of iron and protein deficiency on the anthelmintic efficacy of mebendazole, pyrantel, piperazine, and levamisole. Duncombe, V.M., Bolin, T.D., Davis, A.E., Fagan, M.R., Kelly, J.D. Gut (1979) [Pubmed]
  4. Effect of periodic antiascaris and antigiardia treatment on nutritional status of preschool children. Gupta, M.C., Urrutia, J.J. Am. J. Clin. Nutr. (1982) [Pubmed]
  5. 5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model. Kennett, G.A. Psychopharmacology (Berl.) (1992) [Pubmed]
  6. Effect of 1-(m-chlorophenyl)piperazine and 1-(m-trifluoromethylphenyl)piperazine on locomotor activity. Lucki, I., Ward, H.R., Frazer, A. J. Pharmacol. Exp. Ther. (1989) [Pubmed]
  7. FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, improves visual recognition memory in rhesus monkeys: comparison with physostigmine. Matsuoka, N., Aigner, T.G. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  8. Metabolic activation of a 1,3-disubstituted piperazine derivative: evidence for a novel ring contraction to an imidazoline. Doss, G.A., Miller, R.R., Zhang, Z., Teffera, Y., Nargund, R.P., Palucki, B., Park, M.K., Tang, Y.S., Evans, D.C., Baillie, T.A., Stearns, R.A. Chem. Res. Toxicol. (2005) [Pubmed]
  9. Individual differences in multiple-bag spindles of cat superficial lumbrical muscles. Decorte, L., Emonet-Dénand, F., Harker, D.W., Laporte, Y. J. Anat. (1990) [Pubmed]
  10. Role of protein kinases in stimulation of human polymorphonuclear leukocyte oxidative metabolism by various agonists. Differential effects of a novel protein kinase inhibitor. Gerard, C., McPhail, L.C., Marfat, A., Stimler-Gerard, N.P., Bass, D.A., McCall, C.E. J. Clin. Invest. (1986) [Pubmed]
  11. Nitrosation of piperazine in the stomach. Bellander, B.T., Hagmar, L.E., Osterdahl, B.G. Lancet (1981) [Pubmed]
  12. A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6. Demchyshyn, L., Sunahara, R.K., Miller, K., Teitler, M., Hoffman, B.J., Kennedy, J.L., Seeman, P., Van Tol, H.H., Niznik, H.B. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  13. Dopaminergic therapy improves upper limb motor performance in aged rhesus monkeys. Grondin, R., Zhang, Z., Gerhardt, G.A., Gash, D.M. Ann. Neurol. (2000) [Pubmed]
  14. Intracellular distribution of the Wilson's disease gene product (ATPase7B) after in vitro and in vivo exogenous expression in hepatocytes from the LEC rat, an animal model of Wilson's disease. Nagano, K., Nakamura, K., Urakami, K.I., Umeyama, K., Uchiyama, H., Koiwai, K., Hattori, S., Yamamoto, T., Matsuda, I., Endo, F. Hepatology (1998) [Pubmed]
  15. Flunarizine and cinnarizine inhibit mitochondrial complexes I and II: possible implication for parkinsonism. Veitch, K., Hue, L. Mol. Pharmacol. (1994) [Pubmed]
  16. Synthesis and activity of piperazine-containing antirhinoviral agents and crystal structure of SDZ 880-061 bound to human rhinovirus 14. Oren, D.A., Zhang, A., Nesvadba, H., Rosenwirth, B., Arnold, E. J. Mol. Biol. (1996) [Pubmed]
  17. Ranolazine: a review of its use in chronic stable angina pectoris. Siddiqui, M.A., Keam, S.J. Drugs (2006) [Pubmed]
  18. Novel soluble cationic trans-diaminedichloroplatinum(II) complexes that are active against cisplatin resistant ovarian cancer cell lines. Najajreh, Y., Perez, J.M., Navarro-Ranninger, C., Gibson, D. J. Med. Chem. (2002) [Pubmed]
  19. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist. Tagat, J.R., Steensma, R.W., McCombie, S.W., Nazareno, D.V., Lin, S.I., Neustadt, B.R., Cox, K., Xu, S., Wojcik, L., Murray, M.G., Vantuno, N., Baroudy, B.M., Strizki, J.M. J. Med. Chem. (2001) [Pubmed]
  20. Protein kinase inhibitors selectively block phorbol ester- or forskolin-induced changes in excitability of Aplysia neurons. Conn, P.J., Strong, J.A., Azhderian, E.M., Nairn, A.C., Greengard, P., Kaczmarek, L.K. J. Neurosci. (1989) [Pubmed]
  21. Inhibition of human neutrophil chemotaxis by the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine. Harvath, L., McCall, C.E., Bass, D.A., McPhail, L.C. J. Immunol. (1987) [Pubmed]
  22. Designer DNA-binding drugs: the crystal structure of a meta-hydroxy analogue of Hoechst 33258 bound to d(CGCGAATTCGCG)2. Clark, G.R., Squire, C.J., Gray, E.J., Leupin, W., Neidle, S. Nucleic Acids Res. (1996) [Pubmed]
  23. Photoaffinity labeling of the dopamine reuptake carrier protein with 3-azido[3H]GBR-12935. Berger, S.P., Martenson, R.E., Laing, P., Thurkauf, A., Decosta, B., Rice, K.C., Paul, S.M. Mol. Pharmacol. (1991) [Pubmed]
  24. 5-hydroxytryptamine1A receptor-mediated increases in receptor expression and activation of nuclear factor-kappaB in transfected Chinese hamster ovary cells. Cowen, D.S., Molinoff, P.B., Manning, D.R. Mol. Pharmacol. (1997) [Pubmed]
  25. Formation of primary and secondary myotubes in rat lumbrical muscles. Ross, J.J., Duxson, M.J., Harris, A.J. Development (1987) [Pubmed]
  26. Neural determination of muscle fibre numbers in embryonic rat lumbrical muscles. Ross, J.J., Duxson, M.J., Harris, A.J. Development (1987) [Pubmed]
  27. The effect of selective, chronic stimulation on motor unit size in developing rat muscle. Ridge, R.M., Betz, W.J. J. Neurosci. (1984) [Pubmed]
  28. The origin of secondary myotubes in mammalian skeletal muscles: ultrastructural studies. Duxson, M.J., Usson, Y., Harris, A.J. Development (1989) [Pubmed]
  29. Three serotonin responses in cultured mouse hippocampal and striatal neurons. Yakel, J.L., Trussell, L.O., Jackson, M.B. J. Neurosci. (1988) [Pubmed]
  30. Sprouting of active nerve terminals in partially inactive muscles of the rat. Betz, W.J., Caldwell, J.H., Ribchester, R.R. J. Physiol. (Lond.) (1980) [Pubmed]
  31. Generation of predictive pharmacophore models for CCR5 antagonists: study with piperidine- and piperazine-based compounds as a new class of HIV-1 entry inhibitors. Debnath, A.K. J. Med. Chem. (2003) [Pubmed]
  32. Interferon-gamma-dependent stimulation of Fas antigen in SV40-transformed human keratinocytes: modulation of the apoptotic process by protein kinase C. Takahashi, H., Kobayashi, H., Hashimoto, Y., Matsuo, S., Iizuka, H. J. Invest. Dermatol. (1995) [Pubmed]
  33. Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. Delon, A., Bouquet, S., Huguet, F., Brunet, V., Courtois, P., Couet, W. Antimicrob. Agents Chemother. (1999) [Pubmed]
  34. Characterization of inward-rectifier K+ channel inhibition by antiarrhythmic piperazine. Xu, Y., Lu, Z. Biochemistry (2004) [Pubmed]
  35. Kv3 voltage-gated potassium channels regulate neurotransmitter release from mouse motor nerve terminals. Brooke, R.E., Moores, T.S., Morris, N.P., Parson, S.H., Deuchars, J. Eur. J. Neurosci. (2004) [Pubmed]
  36. Gastric mucosal damage following repeat administration of melanocortin subtype-4 receptor ligands to Fischer 344 rats. Williams, T.M., Donnelly, K.B. Toxicologic pathology (2006) [Pubmed]
  37. Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists. Vu, C.B., Peng, B., Kumaravel, G., Smits, G., Jin, X., Phadke, D., Engber, T., Huang, C., Reilly, J., Tam, S., Grant, D., Hetu, G., Chen, L., Zhang, J., Petter, R.C. J. Med. Chem. (2004) [Pubmed]
  38. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: applying a "divide and conquer" strategy. Ambrose Amin, E., Welsh, W.J. J. Med. Chem. (2001) [Pubmed]
  39. A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. Voziyan, P.A., Metz, T.O., Baynes, J.W., Hudson, B.G. J. Biol. Chem. (2002) [Pubmed]
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  43. Lumbrical sparing in carpal tunnel syndrome: anatomic, physiologic, and diagnostic implications. Logigian, E.L., Busis, N.A., Berger, A.R., Bruyninckx, F., Khalil, N., Shahani, B.T., Young, R.R. Neurology (1987) [Pubmed]
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