Agmatine

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Agmatine
Skeletal formula of an agmatine minor tautomer
Identifiers
CAS number 306-60-5 YesY
PubChem 199
ChemSpider 194 YesY
EC number 206-187-7
KEGG C00179 N
MeSH Agmatine
ChEBI CHEBI:17431 YesY
ChEMBL CHEMBL58343 YesY
3DMet B00052
Jmol-3D images Image 1
Image 2
Properties
Molecular formula C5H14N4
Molar mass 130.19 g mol−1
Density 1.2 g/ml
Melting point 102 °C (216 °F; 375 K)
Boiling point 281 °C (538 °F; 554 K)
Solubility in water high
log P −1.423
Basicity (pKb) 0.52
Hazards
Flash point 95.8 °C (204.4 °F; 368.9 K)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Agmatine, an aminoguanidine ((4-aminobutyl)guanidine), was discovered in 1910 by the Nobel laureate Albrecht Kossel.[2] It is a common natural compound synthesized by decarboxylation of the amino acid arginine, hence also known as decarboxylated arginine.

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 further research into potential applications.

History[edit]

The term "agmatin" (German) was coined in 1910 by Albrecht Kossel who first identified the substance in herring sperm.[3] Most probably the term stems from A- (for amino-) + g- (from guanidine) + -ma- (from ptomaine) + -in (German)/-ine (English) suffix with insertion of -t- apparently for euphony.[4] Within a year following its discovery agmatine has been found to increase blood flow in rabbits,[5] but the physiological relevance of these findings was questioned given the high concentrations (high µM range) required.[6] In the 1920s, researchers in the diabetes clinic of Oskar Minkowski have shown that agmatine can exert mild hypoglycemic effects.[7] The scarcity of research on agmatine during the better part of the 20th century (until the early 1990s) is outstanding. Only in 1994, the discovery of endogenous agmatine synthesis in mammals[8] has revived research in the field.

Metabolic pathways[edit]

Agmatine Metabolic Pathways

Agmatine biosynthesis by arginine decarboxylation is well-positioned to compete with the principal arginine-dependent pathways, namely: nitrogen metabolism (urea cycle), and polyamine and nitric oxide (NO) synthesis (see illustration 'Agmatine Metabolic Pathways'). Agmatine degradation occurs mainly by hydrolysis, catalyzed by agmatinase into urea and putrescine, the diamine precursor of polyamine biosynthesis. An alternative pathway, mainly in peripheral tissues, is by diamine oxidase-catalyzed oxidation into agmatine-aldehyde, which is in turn converted by aldehyde dehydrogenase into guanidinobutyrate and secreted by the kidneys.

Mechanisms of action[edit]

Agmatine was found to exert modulatory actions directly and/or indirectly at multiple key molecular targets underlying cellular control mechanisms of cardinal importance in health and disease. It is considered capable of exerting its modulatory actions simultaneously at these targets, thus fitting the therapeutic profile of a "magic shotgun".[9] The following outline indicates the categories of control mechanisms and identifies their molecular targets:

  • Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2- adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
  • Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+ channels, and acid-sensing ion channels (ASICs).
  • Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system.
  • Nitric oxide (NO) synthesis modulation. Differential inhibition by agmatine of all isoforms of NO synthase (NOS). But induction of endothelial NOS (eNOS).
  • Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.
  • Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.
  • Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.
  • Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.
  • NADPH oxidase. Activation of the enzyme leading to H2O2 production.[10]

Implication in neurotransmission[edit]

Agmatine has been discussed as a putative neurotransmitter/neuromodulator. 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.[11]

Food consumption[edit]

Agmatine sulfate injection can increase food intake with carbohydrate preference in satiated, but not in hungry rats and this effect may be mediated by neuropeptide.[12] However, supplementation in rat drinking water results in reductions in water intake and body weight gain.[13] Also force feeding with agmatine leads to a reduction in body weight gain during rat development.[14]

Pharmacology[edit]

Agmatine is present in small amounts in plant-, animal-, and fish-derived foodstuff and Gut microbial production is an added source for agmatine. Oral agmatine is absorbed from the gastrointestinal tract and readily distributed throughout the body.[15] Rapid elimination of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours.[16]

Weight gain changes were not observed during human clinical trials in individuals taking oral agmatine sulfate for up to 21 days.[17]

Agmatine sulfate supplements have been marketed for several years now to the bodybuilding channel, touting muscle-building qualities, although using completely unsubstantiated claims.

Research[edit]

Based on laboratory studies using in vitro and in vivo models there are a number of potential research opportunities for agmatine.[18]

Cardiovascular[edit]

Agmatine produces mild reductions in heart rate and blood pressure, apparently by activating both central and peripheral control systems via modulation of several of its molecular targets including: imidazoline receptors subtypes, norepinephrine release and NO production.[19]

Glucose regulation[edit]

Agmatine hypoglycemic effects, known since the 1920s,[20] are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.[21]

Kidney functions[edit]

Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.[22]

Opioid liability[edit]

Systemic agmatine can potentiate opioid analgesia and prevent tolerance to chronic morphine in laboratory rodents. Since then, cumulative evidence amply shows that agmatine inhibits opioid dependence and relapse in several animal species.[23]

Behavioral effects[edit]

Antidepressant properties[edit]

Agmatine administrations dose-responsively produce antidepressant-like behaviors in laboratory animals, which probably involve modulation of several neurotransmitter receptors (including: NMDAr, α2-adrenoceptors, serotonin, δ- and μ-opioid, and imidazoline receptors).[24][25]

Schizophrenia[edit]

In animal models of schizophrenia, agmatine can attenuate characteristic behavioral patterns and potentiate the inhibitory effect of known antipsychotics (haloperidol and olanzepine).[26][27]

See also[edit]

References[edit]

  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. ^ Kossel, Albrecht 1910. Über das Agmatin. Zeitschrift für Physiologische Chemie 66: 257-261
  4. ^ "agmantine". Oxford English Dictionary (3rd ed.). Oxford University Press. September 2005. 
  5. ^ Engeland, R. and Kutscher, F., (1910) Ueber eine zweite wirksame Secale-base. Zeitschr Physiol Chem 57, 49-65
  6. ^ Dale, H.H. and Laidlaw, P.P., (1911) Further observations on the action of β-iminazolylethylamine. J Physiol 43, 182–95
  7. ^ Frank, E. Nothmann, M. Wagner, A. (1926) Uber synthetisch dargestellte korper mit insulinartiger wirkung auf den normalen und diabetischen organismus. Klinische Wochenschrift 5 (45): 2100-2107]
  8. ^ Li, G., Regunathan, S., Barrow, C.J., Eshraghi, J., Cooper, R., and Reis., D.J. 1994. Agmatine: An endogenous clonidine-displacing substance in the brain. Science 263:966-969
  9. ^ Piletz JE, Aricioglu F, Cheng J-T, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues ALS, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM. Agmatine: clinical applications after 100 years in translation. Drug Discovery Today 18 (17-18):880-893, 2013. doi:10.1016/j.drudis.2013.05.017
  10. ^ 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. 
  11. ^ 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
  12. ^ Taksande B.G., Kotagale N.R., Nakhate K.T., Mali P.D., Kokare D.M., Hirani K., Subheda, N.K., Chopde C.T., Ugale R.R. (2011) Agmatine in the hypothalamic-paraventricular nucleus stimulates feeding in rats: Involvement of neuropeptide Y. British Journal of Pharmacology 164: 704-718
  13. ^ Gilad G.M., Gilad V.H. (2013) Evidence for oral agmatine sulfate safety – A 95-day high dosage pilot study with rats. Food Chemistry and Toxicology 62C:758-762
  14. ^ Nissim I., Horyn O., Daikhin Y., Chen P., Li C., Wehrli S.L., Nissim I., Yudkoff M. (2014) The molecular and metabolic influence of long term agmatine consumption. Journal of Biological Chemistry 289(14): 9710-9729
  15. ^ Haenisch B., von Kügelgen I., Bönisch H., Göthert M., Sauerbruch T., Schepke M., Marklein G., Höfling K., Schröder D., Molderings G.J. (2008) Regulatory mechanisms underlying agmatine homeostasis in humans. American Journal of Physiology Gastrointestinal Liver Physiology 295, G1104-G1110
  16. ^ Huisman H., Wynveen P., Nichkova M., Kellermann G. (2010) Novel ELISAs for screening of the biogenic amines GABA, glycine, beta-phenylethylamine, agmatine, and taurine using one derivatization procedure of whole urine samples. Anayticall Chemistry 82, 6526-6533
  17. ^ Keynan O., Mirovsky Y., Dekel S., Gilad V.H., Gilad G.M. (2010) 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, 11:356–368
  18. ^ Halaris, A; Plietz, J (2007). "Agmatine : metabolic pathway and spectrum of activity in brain.". CNS drugs 21 (11): 885–900. PMID 17927294. 
  19. ^ Raasch, W., Schafer, U., Chun, J., and Dominiak, P. (2001) Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. British Journal of Pharmacology 133, 755-80
  20. ^ Frank, E. Nothmann, M. Wagner, A. (1926) Uber synthetisch dargestellte korper mit insulinartiger wirkung auf den normalen und diabetischen organismus. Klinische Wochenschrift 5 (45): 2100-2107
  21. ^ Piletz JE, Aricioglu F, Cheng J-T, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues ALS, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM. Agmatine: clinical applications after 100 years in translation. Drug Discovery Today 18 (17-18):880-893, 2013. (DOI information: 10.1016/j.drudis.2013.05.017)
  22. ^ Satriano J. (2004) Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 26, 321-329
  23. ^ Su RB, Li J, Qin BY. A biphasic opioid function modulator: agmatine. Acta Pharmacol Sin. (2003),
  24. ^ Zomkowski A.D., Hammes L., Lin J., Calixto J.B., Santos A.R., Rodrigues A.L. (2002) Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport 13, 387-391,
  25. ^ 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. 
  26. ^ Pålsson E., Fejgin K., Wass C., Klamer D. (2008) Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition. European Journal of Pharmacology 590, 212-216,
  27. ^ Kotagale N.R., Taksande B.G., Wadhwani P.J., Palhade M.W., Mendhi S.M., Gawande D.Y., Hadole P.N., Chopde C.T. (2012) Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents. Pharmacology Biochemistry and Behavior 100, 398-403

External links[edit]

  • 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.