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Agmatine

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Agmatine
Skeletal formula of an agmatine minor tautomer
Names
IUPAC name
1-(4-Aminobutyl)guanidine[1]
Identifiers
3D model (JSmol)
3DMet
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.626 Edit this at Wikidata
EC Number
  • 206-187-7
KEGG
MeSH Agmatine
  • InChI=1S/C5H14N4/c6-3-1-2-4-9-5(7)8/h1-4,6H2,(H4,7,8,9) checkY
    Key: QYPPJABKJHAVHS-UHFFFAOYSA-N checkY
  • NCCCC[nH]:c(:[nH]):[nH2]
  • NCCCCNC(N)=N
Properties
C5H14N4
Molar mass 130.195 g·mol−1
Density 1.2 g/ml
Melting point 102 °C (216 °F; 375 K)
Boiling point 281 °C (538 °F; 554 K)
high
log P −1.423
Basicity (pKb) 0.52
Hazards
Flash point 95.8 °C (204.4 °F; 368.9 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Agmatine an aminoguanidine ((4-aminobutyl)guanidine), is a ubiquitous natural compound synthesized by decarboxylation of the amino acid arginine and is a precursor of polyamine biosynthesis. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, key ion channels, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications.

History

The term "agmatine" was coined in 1910 by Albrecht Kossel, the German scientist who first identified the substance in herring sperm.[2] Most probably the word stems from A- (for amino-) + g- (from guanidine) + -ma- (from ptomaine) + -in (German)/-ine (English) suffix with insertion of -t- apparently for euphony.[3]

Implication in Neurotransmission

Agmatine has been discussed as a putative neurotransmitter. It is synthesized in the brain, stored in synaptic vesicles, accumulated by uptake, released by membrane depolarization, and inactivated by agmatinase. Agmatine binds to α2-adrenergic receptor and imidazoline receptor binding sites, and blocks NMDA receptors and other cation ligand-gated channels. Short only of identifying specific ("own") post-synaptic receptors, agmatine in fact, fulfills Henry Dale's criteria for a neurotransmitter and is hence, considered a neuromodulator and co-transmitter. But identification of agmatinergic neuronal systems, if exist, still awaits future research.[4]

Effects on nitric oxide synthase (NOS)

An in vitro study found that agmatine was a competitive inhibitor of NOS, with enzyme-inhibitor concentrations (Ki) 660 μM for NOS I (neuronal NOS), 220 μM for NOS II (inducible NOS), and 7.5 mM for NOS III (endothelial NOS).[5] Another study determined that concentrations of agmatine on the order of 29 μM effect an irreversible, time- and concentration-dependent inactivation of NOS I. The same study noted a threefold increase in NADPH oxidase activity and accompanying oxidative stress via H2O2 production.[6]

Neuroprotective effect

Treatment with exogenous agmatine exerts neuroprotective effects in animal models of ischemia and neurotrauma.[7]

Treatment of neuropathic pain

Supplementation of agmatine has been shown to reduce neuropathic pain in rats.[8][9] A human study has demonstrated effectiveness of agmatine against neuropathic pain in the form of radiculopathy.[10]

Antidepressant potential

A recent study shows that agmatine administered orally abolished the depressive-like behavior induced by the administration of the pro-inflammatory cytokine, tumor necrosis factor (TNF-α) in mice.[11]

Another study shows that oral agmatine exerts antidepressant like effects via NPYergic system possibly mediated by the NPY Y1 receptor subtypes in rats.[12] Two earlier studies from the same author show that activation of the δ-opioid and μ-opioid receptor[13] and the 5-HT1A, 5-HT1B and 5-HT2 receptors are important for the antidepressant effect of agmatine.

Two other studies in mice show that agmatine binding to the imidazoline receptor is involved in the antidepressant action of both NDRI bupropion[14] and the SSRIs fluoxetine and paroxetine.[15] Indeed, another study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I1 and I2 receptors.[16]

See also

References

  1. ^ "agmatine (CHEBI:17431)". Chemical Entities of Biological Interest. UK: European Bioinformatics Institute. 15 August 2008. Main. Retrieved 11 January 2012.
  2. ^ Kossel, Albrecht 1910. Über das Agmatin. Zeitschrift für Physiologische Chemie 66: 257-261
  3. ^ "agmantine". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
  4. ^ Agmatine: clinical applications after 100 years in translation. Drug Discovery Today 2013 Sep;18(17-18):880-93. doi: 10.1016/j.drudis.2013.05.017. Epub 2013 Jun 13
  5. ^ Galea, E.; Regunathan, S.; Eliopoulos, V.; Feinstein, D.L.; Reis, D.J. (1996). "Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine". Biochemical Journal. 316 (1): 247–249. PMID 8645212.
  6. ^ Demady, DR.; Jianmongkol, S.; Vuletich, JL.; Bender, AT.; Osawa, Y. (2001). "Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme". Molecular Pharmacology. 59 (1): 24–9. PMID 11125020.
  7. ^ Kim, J.H.; Yenari, M.A.; Giffard, R.G.; Cho, S.W.; Park, K.A.; Lee, J.E. (2004). "Agmatine reduces infarct area in a mouse model of transient focal cerebral ischemia and protects cultured neurons from ischemia-like injury". Experimental Neurology. 189 (1): 122–30. doi:10.1016/j.expneurol.2004.05.029. PMID 15296842.
  8. ^ Fairbanks CA, et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A. (2000)
  9. ^ Su RB, Li J, Qin BY. A biphasic opioid function modulator: agmatine. Acta Pharmacol Sin. (2003)
  10. ^ Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial. Pain Medicine 2010 Mar;11(3):356-68.
  11. ^ Neis, Vivian Binder; Manosso, Luana Meller; Moretti, Morgana; Freitas, Andiara E.; Daufenbach, Juliana; Rodrigues, Ana Lúcia S. (2014). "Depressive-like behavior induced by tumor necrosis factor-α is abolished by agmatine administration". Behavioural Brain Research. 261C: 336–344. doi:10.1016/j.bbr.2013.12.038. PMID 24406719.
  12. ^ Kotagale, Nandkishor R.; Paliwal, Nikhilesh P.; Aglawe, Manish M.; Umekar, Milind J.; Taksande, Brijesh G. (2013). "Possible involvement of neuropeptide Y Y1 receptors in antidepressant like effect of agmatine in rats". Peptides. 47: 7–11. doi:10.1016/j.peptides.2013.04.018. PMID 23816796.
  13. ^ Zomkowski, Andrea D.E.; Santos, Adair R.S.; Rodrigues, Ana L.S. (2005). "Evidence for the involvement of the opioid system in the agmatine antidepressant-like effect in the forced swimming test". Neuroscience Letters. 381 (3): 279–83. doi:10.1016/j.neulet.2005.02.026. PMID 15896484.
  14. ^ Kotagale, Nandkishor R.; Tripathi, Sunil J.; Aglawe, Manish M.; Chopde, Chandrabhan T.; Umekar, Milind J.; Taksande, Brijesh G. (2013). "Evidences for the agmatine involvement in antidepressant like effect of bupropion in mouse forced swim test". Pharmacology Biochemistry and Behavior. 107: 42–7. doi:10.1016/j.pbb.2013.03.019. PMID 23583442.
  15. ^ Bernstein, Hans-Gert; Stich, Claudia; Jäger, Kristin; Dobrowolny, Henrik; Wick, Martin; Steiner, Johann; Veh, Rüdiger; Bogerts, Bernhard; Laube, Gregor (2012). "Agmatinase, an inactivator of the putative endogenous antidepressant agmatine, is strongly upregulated in hippocampal interneurons of subjects with mood disorders". Neuropharmacology. 62 (1): 237–46. doi:10.1016/j.neuropharm.2011.07.012. PMID 21803059. {{cite journal}}: Invalid |display-authors=9 (help)
  16. ^ Zeidan, Mariana P.; Zomkowski, Andréa D.E.; Rosa, Angelo O.; Rodrigues, Ana Lúcia S.; Gabilan, Nelson H. (2007). "Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test". European Journal of Pharmacology. 565 (1–3): 125–31. doi:10.1016/j.ejphar.2007.03.027. PMID 17445795.
  • Wilcox, G.; Fiska, A.; Haugan, F.; Svendsen, F.; Rygh, L.; Tjolsen, A.; Hole, K. (2004). "Central sensitization: The endogenous NMDA antagonist and NOS inhibitor agmatine inhibits spinal long term potentiation (LTP)". The Journal of Pain. 5 (3): S19. doi:10.1016/j.jpain.2004.02.041.
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