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Agmatine
Names
	IUPAC name 1-(4-Aminobutyl)guanidine
Identifiers
CAS Number	306-60-5 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:17431 ;
ChEMBL	ChEMBL58343 ;
ChemSpider	194 ;
ECHA InfoCard	100.005.626
EC Number	206-187-7;
KEGG	C00179 ;
MeSH	Agmatine
PubChem CID	199;
UNII	70J407ZL5Q ;
CompTox Dashboard (EPA)	DTXSID0040961 ;
	InChI InChI=1S/C5H14N4/c6-3-1-2-4-9-5(7)8/h1-4,6H2,(H4,7,8,9) Key: QYPPJABKJHAVHS-UHFFFAOYSA-N ;
	SMILES NCCCCNC(N)=N;
Properties
Chemical formula	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)
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 otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) 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 showed that agmatine can exert mild hypoglycemic effects.^[6] In 1994, endogenous agmatine synthesis in mammals was discovered.^[7]

Metabolic pathways

Agmatine is a cationic amine formed by decarboxylation of L-arginine by the mitochondrial enzyme arginine decarboxylase (ADC).^[8] Agmatine degradation occurs mainly by hydrolysis, catalyzed by agmatinase into urea and putrescine, the diamine precursor of polyamine biosynthesis.^[9] 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.^[10]

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.^[11] 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. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.^[12]^[13]
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.^[14]

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.^[15] However, supplementation in rat drinking water results in slight reductions in water intake, body weight, and blood pressure.^[16] In addition, force feeding with agmatine leads to a reduction in body weight gain during rat development.^[17] It is also found that many fermented foods contain agmatine.^[18]^[19]

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.^[20] Rapid elimination from non-brain organs of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours.^[21]

Research

A number of potential medical uses for agmatine have been suggested.^[22]

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.^[23]

Glucose regulation

Agmatine hypoglycemic effects are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.^[11]

Kidney functions

Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.^[24]

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.^[25]^[26] 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.^[11] 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.^[27] 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.^[28]

References

^ "agmatine (CHEBI:17431)". Chemical Entities of Biological Interest. UK: European Bioinformatics Institute. 15 August 2008. Main. Retrieved 11 January 2012.
^ Kossel A (1910). "Über das Agmatin". Zeitschrift für Physiologische Chemie (in German). 66 (3): 257–261. doi:10.1515/bchm2.1910.66.3.257.
^ "agmantine". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
^ Engeland R, Kutscher F (1910). "Ueber eine zweite wirksame Secale-base". Z Physiol Chem (in German). 57: 49–65. doi:10.1515/bchm2.1908.57.1-2.49.
^ Dale HH, Laidlaw PP (October 1911). "Further observations on the action of beta-iminazolylethylamine". The Journal of Physiology. 43 (2): 182–95. doi:10.1113/jphysiol.1911.sp001464. PMC 1512691. PMID 16993089.
^ Frank E, Nothmann M, Wagner A (1926). "über Synthetisch Dargestellte Körper mit Insulinartiger Wirkung Auf den Normalen und Diabetischen Organismus". Klinische Wochenschrift (in German). 5 (45): 2100–2107. doi:10.1007/BF01736560. S2CID 35090913.
^ Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ (February 1994). "Agmatine: an endogenous clonidine-displacing substance in the brain". Science. 263 (5149): 966–9. Bibcode:1994Sci...263..966L. doi:10.1126/science.7906055. PMID 7906055.
^ Molderings GJ, Haenisch B (2012-03-01). "Agmatine (decarboxylated l-arginine): Physiological role and therapeutic potential". Pharmacology & Therapeutics. 133 (3): 351–365. doi:10.1016/j.pharmthera.2011.12.005. ISSN 0163-7258.
^ Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues AL, Satriano J, Seong GJ (2013-09-01). "Agmatine: clinical applications after 100 years in translation". Drug Discovery Today. 18 (17): 880–893. doi:10.1016/j.drudis.2013.05.017. ISSN 1359-6446.
^ Satriano J, Schwartz D, Ishizuka S, Lortie M (September 2001). "Suppression of inducible nitric oxide generation by agmatine aldehyde: Beneficial effects in sepsis". ResearchGate.
^ ^a ^b ^c Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues AL, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM (September 2013). "Agmatine: clinical applications after 100 years in translation". Drug Discovery Today. 18 (17–18): 880–93. doi:10.1016/j.drudis.2013.05.017. PMID 23769988.
^ Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ (1996-05-15). "Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine". Biochemical Journal. 316 (1): 247–249. doi:10.1042/bj3160247. ISSN 0264-6021. PMC 1217329. PMID 8645212.
^ Gadkari TV, Cortes N, Madrasi K, Tsoukias NM, Joshi MS (November 2013). "Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension". Nitric Oxide. 35: 65–71. doi:10.1016/j.niox.2013.08.005. PMC 3844099. PMID 23994446.
^ Demady DR, Jianmongkol S, Vuletich JL, Bender AT, Osawa Y (January 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. doi:10.1124/mol.59.1.24. PMID 11125020. S2CID 16298942.
^ Taksande BG, Kotagale NR, Nakhate KT, Mali PD, Kokare DM, Hirani K, Subhedar NK, Chopde CT, Ugale RR (September 2011). "Agmatine in the hypothalamic paraventricular nucleus stimulates feeding in rats: involvement of neuropeptide Y". British Journal of Pharmacology. 164 (2b): 704–18. doi:10.1111/j.1476-5381.2011.01484.x. PMC 3188911. PMID 21564088.
^ Gilad GM, Gilad VH (December 2013). "Evidence for oral agmatine sulfate safety--a 95-day high dosage pilot study with rats". Food and Chemical Toxicology. 62: 758–62. doi:10.1016/j.fct.2013.10.005. PMID 24140462.
^ Nissim I, Horyn O, Daikhin Y, Chen P, Li C, Wehrli SL, Nissim I, Yudkoff M (April 2014). "The molecular and metabolic influence of long term agmatine consumption". The Journal of Biological Chemistry. 289 (14): 9710–29. doi:10.1074/jbc.M113.544726. PMC 3975019. PMID 24523404.
^ Galgano F, Caruso M, Condelli N, Favati F (2012-06-07). "Focused review: agmatine in fermented foods". Frontiers in Microbiology. 3: 199. doi:10.3389/fmicb.2012.00199. PMC 3369198. PMID 22701114.
^ 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.
^ Haenisch B, von Kügelgen I, Bönisch H, Göthert M, Sauerbruch T, Schepke M, Marklein G, Höfling K, Schröder D, Molderings GJ (November 2008). "Regulatory mechanisms underlying agmatine homeostasis in humans". American Journal of Physiology. Gastrointestinal and Liver Physiology. 295 (5): G1104-10. doi:10.1152/ajpgi.90374.2008. PMID 18832451.
^ Huisman H, Wynveen P, Nichkova M, Kellermann G (August 2010). "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. doi:10.1021/ac100858u. PMID 20586417.
^ Halaris A, Plietz J (2007). "Agmatine : metabolic pathway and spectrum of activity in brain". CNS Drugs. 21 (11): 885–900. doi:10.2165/00023210-200721110-00002. PMID 17927294.
^ Raasch W, Schäfer U, Chun J, Dominiak P (July 2001). "Biological significance of agmatine, an endogenous ligand at imidazoline binding sites". British Journal of Pharmacology. 133 (6): 755–80. doi:10.1038/sj.bjp.0704153. PMC 1572857. PMID 11454649.
^ Satriano J (July 2004). "Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article". Amino Acids. 26 (4): 321–9. doi:10.1007/s00726-004-0078-4. PMID 15290337. S2CID 23116711.
^ Pinthong D, Wright IK, Hanmer C, Millns P, Mason R, Kendall DA, Wilson VG (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. S2CID 20785398.
^ Pineda J, Ruiz-Ortega JA, 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. S2CID 32456961.
^ Marc RE (April 1999). "Mapping glutamatergic drive in the vertebrate retina with a channel-permeant organic cation". The Journal of Comparative Neurology. 407 (1): 47–64. doi:10.1002/(sici)1096-9861(19990428)407:1<47::aid-cne4>3.0.co;2-0. PMID 10213187. S2CID 15955446.
^ Su RB, Li J, Qin BY (July 2003). "A biphasic opioid function modulator: agmatine". Acta Pharmacologica Sinica. 24 (7): 631–6. PMID 12852826.