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Agmatine

Topic: Chemistry

 From HandWiki - Reading time: 11 min
Agmatine
Skeletal formula of agmatine
Names
IUPAC name
1-(4-Aminobutyl)guanidine[1]
Identifiers
3D model (JSmol)
3DMet
ChEBI
ChEMBL
ChemSpider
EC Number
  • 206-187-7
KEGG
MeSH Agmatine
UNII
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).
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Infobox references

Agmatine, also known as 4-aminobutyl-guanidine, was discovered in 1910 by Albrecht Kossel.[2] It is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism and this provides bases for further research into potential applications.

History

The term agmatine stems from A- (for amino-) + g- (from guanidine) + -ma- (from ptomaine) + -in (German)/-ine (English) suffix with insertion of -t- apparently for euphony.[3] A year after its discovery, it was found that Agmatine could increase blood flow in rabbits;[4] however, the physiological relevance of these findings were questioned given the high concentrations (high μM range) required.[5] In the 1920s, researchers in the diabetes clinic of Oskar Minkowski have shown that agmatine can exert mild hypoglycemic effects.[6] In 1994, endogenous agmatine synthesis in mammals was discovered.[7]

Metabolic pathways

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

Agmatine was found to exert modulatory actions directly and 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 multiple targets.[8] 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 (no intrinsic activity—neither agonist nor antagonist[non sequitur]), 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. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.[9][10]
  • 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.[11]

Food consumption

Agmatine sulfate injection can increase food intake with carbohydrate preference in satiated, but not hungry, rats and this effect may be mediated by neuropeptide Y.[12] However, supplementation in rat drinking water results in slight reductions in water intake, body weight, and blood pressure.[13] In addition, force feeding with agmatine leads to a reduction in body weight gain during rat development.[14] It is also found that many fermented foods contain agmatine.[15][16]

Pharmacokinetics

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.[17] Rapid elimination from non-brain organs of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours.[18]

Research

A number of potential medical uses for agmatine have been suggested.[19]

Cardiovascular

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.[20]

Glucose regulation

Agmatine hypoglycemic effects are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.[8]

Kidney functions

Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.[21]

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. However, while agmatine binds to α2-adrenergic receptors, it exerts neither an agonistic nor antagonistic effect on these receptors, lacking any intrinsic activity.[22][23] Short only of identifying specific ("own") post-synaptic receptors, agmatine fulfills Henry Dale's criteria for a neurotransmitter and is hence considered a neuromodulator and co-transmitter. The existence of theoretical agmatinergic-mediated neuronal systems has not yet been demonstrated although the existence of such receptors is implied by its prominence in the mediation of both the central and peripheral nervous systems.[8] Research into agmatine-specific receptors and transmission pathways continues.

Due to its ability to pass through open cationic channels, agmatine has also been used as a surrogate metric of integrated ionic flux into neural tissue upon stimulation.[24] When neural tissue is incubated in agmatine and an external stimulus is applied, only cells with open channels will be filled with agmatine, allowing identification of which cells are sensitive to that stimuli and the degree to which they opened their cationic channels during the stimulation period.

Opioid liability

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.[25]

See also

References

  1. ↑ "agmatine (CHEBI:17431)". Chemical Entities of Biological Interest. UK: European Bioinformatics Institute. 15 August 2008. Main. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=17431. 
  2. ↑ "Über das Agmatin" (in de). Zeitschrift für Physiologische Chemie 66 (3): 257–261. 1910. doi:10.1515/bchm2.1910.66.3.257. http://vlp.mpiwg-berlin.mpg.de/references?id=lit18967. 
  3. ↑ agmantine (3rd ed.), Oxford University Press, September 2005, http://oed.com/search?searchType=dictionary&q=agmantine  (Subscription or UK public library membership required.)
  4. ↑ "Ueber eine zweite wirksame Secale-base." (in de). Z Physiol Chem 57: 49–65. 1910. doi:10.1515/bchm2.1908.57.1-2.49. https://zenodo.org/record/1627042. 
  5. ↑ "Further observations on the action of beta-iminazolylethylamine". The Journal of Physiology 43 (2): 182–95. October 1911. doi:10.1113/jphysiol.1911.sp001464. PMID 16993089. 
  6. ↑ "über Synthetisch Dargestellte Körper mit Insulinartiger Wirkung Auf den Normalen und Diabetischen Organismus" (in de). Klinische Wochenschrift 5 (45): 2100–2107. 1926. doi:10.1007/BF01736560. 
  7. ↑ "Agmatine: an endogenous clonidine-displacing substance in the brain". Science 263 (5149): 966–9. February 1994. doi:10.1126/science.7906055. PMID 7906055. Bibcode: 1994Sci...263..966L. 
  8. ↑ 8.0 8.1 8.2 "Agmatine: clinical applications after 100 years in translation". Drug Discovery Today 18 (17–18): 880–93. September 2013. doi:10.1016/j.drudis.2013.05.017. PMID 23769988. 
  9. ↑ Galea, Elena; Regunathan, S.; Eliopoulos, Vassily; Feinstein, Douglas L.; Reis, Donald J. (1996-05-15). "Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine" (in en). Biochemical Journal 316 (1): 247–249. doi:10.1042/bj3160247. ISSN 0264-6021. PMID 8645212. 
  10. ↑ "Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension". Nitric Oxide 35: 65–71. November 2013. doi:10.1016/j.niox.2013.08.005. PMID 23994446. 
  11. ↑ "Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme". Molecular Pharmacology 59 (1): 24–9. January 2001. doi:10.1124/mol.59.1.24. PMID 11125020. 
  12. ↑ "Agmatine in the hypothalamic paraventricular nucleus stimulates feeding in rats: involvement of neuropeptide Y". British Journal of Pharmacology 164 (2b): 704–18. September 2011. doi:10.1111/j.1476-5381.2011.01484.x. PMID 21564088. 
  13. ↑ "Evidence for oral agmatine sulfate safety--a 95-day high dosage pilot study with rats". Food and Chemical Toxicology 62: 758–62. December 2013. doi:10.1016/j.fct.2013.10.005. PMID 24140462. 
  14. ↑ "The molecular and metabolic influence of long term agmatine consumption". The Journal of Biological Chemistry 289 (14): 9710–29. April 2014. doi:10.1074/jbc.M113.544726. PMID 24523404. 
  15. ↑ "Focused review: agmatine in fermented foods". Frontiers in Microbiology 3: 199. 2012-06-07. doi:10.3389/fmicb.2012.00199. PMID 22701114. 
  16. ↑ Wang, Che-Chuan. "Beneficial Effect of Agmatine on Brain Apoptosis, Astrogliosis, and Edema after Rat Transient Cerebral Ischemia." BMC Pharmacology. BioMed Central, 6 Sept. 2010. Web. 03 Mar. 2016.
  17. ↑ "Regulatory mechanisms underlying agmatine homeostasis in humans". American Journal of Physiology. Gastrointestinal and Liver Physiology 295 (5): G1104-10. November 2008. doi:10.1152/ajpgi.90374.2008. PMID 18832451. 
  18. ↑ "Novel ELISAs for screening of the biogenic amines GABA, glycine, beta-phenylethylamine, agmatine, and taurine using one derivatization procedure of whole urine samples". Analytical Chemistry 82 (15): 6526–33. August 2010. doi:10.1021/ac100858u. PMID 20586417. 
  19. ↑ "Agmatine : metabolic pathway and spectrum of activity in brain". CNS Drugs 21 (11): 885–900. 2007. doi:10.2165/00023210-200721110-00002. PMID 17927294. 
  20. ↑ "Biological significance of agmatine, an endogenous ligand at imidazoline binding sites". British Journal of Pharmacology 133 (6): 755–80. July 2001. doi:10.1038/sj.bjp.0704153. PMID 11454649. 
  21. ↑ "Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article". Amino Acids 26 (4): 321–9. July 2004. doi:10.1007/s00726-004-0078-4. PMID 15290337. 
  22. ↑ Pinthong, D.; Wright, I. K.; Hanmer, C.; Millns, P.; Mason, R.; Kendall, D. A.; Wilson, V. G. (January 1995). "Agmatine recognizes alpha 2-adrenoceptor binding sites but neither activates nor inhibits alpha 2-adrenoceptors". Naunyn-Schmiedeberg's Archives of Pharmacology 351 (1): 10–16. doi:10.1007/BF00169058. ISSN 0028-1298. PMID 7715734. https://pubmed.ncbi.nlm.nih.gov/7715734/. 
  23. ↑ Pineda, J.; Ruiz-Ortega, J. A.; Martín-Ruiz, R.; Ugedo, L. (1996-11-22). "Agmatine does not have activity at alpha 2-adrenoceptors which modulate the firing rate of locus coeruleus neurones: an electrophysiological study in rat". Neuroscience Letters 219 (2): 103–106. doi:10.1016/s0304-3940(96)13180-3. ISSN 0304-3940. PMID 8971790. https://pubmed.ncbi.nlm.nih.gov/8971790/. 
  24. ↑ "Mapping glutamatergic drive in the vertebrate retina with a channel-permeant organic cation". The Journal of Comparative Neurology 407 (1): 47–64. April 1999. doi:10.1002/(sici)1096-9861(19990428)407:1<47::aid-cne4>3.0.co;2-0. PMID 10213187. 
  25. ↑ "A biphasic opioid function modulator: agmatine". Acta Pharmacologica Sinica 24 (7): 631–6. July 2003. PMID 12852826. http://www.chinaphar.com/article/view/9162/9833. 

Further reading

  • 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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