View source for Agmatine

{{distinguish|agmatidine|arginine}}
{{cs1 config|name-list-style=vanc}}
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| verifiedrevid = 477243638
| ImageFile = Agmatine.svg
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| ImageName = Skeletal formula of agmatine
| IUPACName = 1-(4-Aminobutyl)guanidine<ref>{{cite web|title=agmatine (CHEBI:17431)|url=https://www.ebi.ac.uk/chebi/searchId.do?chebiId=17431|work=Chemical Entities of Biological Interest|publisher=European Bioinformatics Institute|access-date=11 January 2012|location=UK|date=15 August 2008|at=Main}}</ref>
|Section1={{Chembox Identifiers
| CASNo = 306-60-5
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 70J407ZL5Q
| PubChem = 199
| ChemSpiderID = 194
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| EINECS = 206-187-7
| KEGG = C00179
| KEGG_Ref = {{keggcite|correct|kegg}}
| MeSHName = Agmatine
| ChEBI = 17431
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 58343
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| 3DMet = B00052
| SMILES = NCCCCNC(N)=N
| StdInChI = 1S/C5H14N4/c6-3-1-2-4-9-5(7)8/h1-4,6H2,(H4,7,8,9)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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|Section2={{Chembox Properties
| C=5 | H=14 | N=4 
| LogP = −1.423
| Density = 1.2 g/ml
| MeltingPtC = 102
| BoilingPtC = 281
| Solubility = high
| pKb = 0.52
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|Section3={{Chembox Hazards
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|Section4={{Chembox Related
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'''Agmatine''', also known as '''4-aminobutyl-guanidine''', was discovered in 1910 by [[Albrecht Kossel]].<ref name = "Kossel_1910">{{cite journal | vauthors = Kossel A | year = 1910 | url = http://vlp.mpiwg-berlin.mpg.de/references?id=lit18967 | title = Über das Agmatin | journal = Zeitschrift für Physiologische Chemie | volume = 66 | issue = 3 | pages = 257–261 | language = de | doi=10.1515/bchm2.1910.66.3.257}}</ref> 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 target]]s, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis, and [[polyamine]] metabolism and this provides bases for further research into potential pharmacological 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]].<ref>{{OED|agmantine}}</ref> A year after its discovery, it was found that agmatine could increase blood flow in rabbits;<ref>{{cite journal |vauthors=Engeland R, Kutscher F | year = 1910 | title = Ueber eine zweite wirksame Secale-base. | journal = Z Physiol Chem | volume = 57 | pages = 49–65 | language = de | doi = 10.1515/bchm2.1908.57.1-2.49 | url =https://zenodo.org/record/1627042 }}<!--https://zenodo.org/record/1627042--></ref> however, the physiological relevance of these findings were questioned given the high concentrations (high [[Micromolar|μM]] range) required.<ref name="pmid16993089">{{cite journal | vauthors = Dale HH, Laidlaw PP | title = Further observations on the action of beta-iminazolylethylamine | journal = The Journal of Physiology | volume = 43 | issue = 2 | pages = 182–95 | date = October 1911 | pmid = 16993089 | pmc = 1512691 | doi = 10.1113/jphysiol.1911.sp001464 }}</ref> In the 1920s, researchers in the diabetes clinic of [[Oskar Minkowski]] showed that agmatine can exert mild [[hypoglycemic]] effects.<ref name = "Frank_1926">{{cite journal |vauthors=Frank E, Nothmann M, Wagner A | title = über Synthetisch Dargestellte Körper mit Insulinartiger Wirkung Auf den Normalen und Diabetischen Organismus | journal = Klinische Wochenschrift | year =1926 | volume=5 | issue = 45 | pages = 2100–2107 | doi = 10.1007/BF01736560 | s2cid = 35090913 | language = de  }}</ref>  In 1994, endogenous agmatine synthesis in mammals was discovered.<ref name="pmid7906055">{{cite journal | vauthors = Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ | title = Agmatine: an endogenous clonidine-displacing substance in the brain | journal = Science | volume = 263 | issue = 5149 | pages = 966–9 | date = February 1994 | pmid = 7906055 | doi = 10.1126/science.7906055 | bibcode = 1994Sci...263..966L }}</ref>

==Metabolic pathways==
[[File:Wikipedia-Agmatine Metabolic Pathways.jpg|thumb|upright=1.35|Agmatine Metabolic Pathways]]
Agmatine is a cationic [[amine]] formed by [[decarboxylation]] of L-arginine by the mitochondrial enzyme arginine decarboxylase (ADC).<ref>{{Cite journal |last1=Molderings |first1=Gerhard J. |last2=Haenisch |first2=Britta |date=2012-03-01 |title=Agmatine (decarboxylated l-arginine): Physiological role and therapeutic potential |url=https://www.sciencedirect.com/science/article/pii/S0163725811002282 |journal=Pharmacology & Therapeutics |volume=133 |issue=3 |pages=351–365 |doi=10.1016/j.pharmthera.2011.12.005 |issn=0163-7258|url-access=subscription }}</ref> Agmatine degradation occurs mainly by hydrolysis, catalyzed by [[agmatinase]] into [[urea]] and [[putrescine]], the diamine precursor of [[polyamine]] biosynthesis.<ref>{{Cite journal |last1=Piletz |first1=John E. |last2=Aricioglu |first2=Feyza |last3=Cheng |first3=Juei-Tang |last4=Fairbanks |first4=Carolyn A. |last5=Gilad |first5=Varda H. |last6=Haenisch |first6=Britta |last7=Halaris |first7=Angelos |last8=Hong |first8=Samin |last9=Lee |first9=Jong Eun |last10=Li |first10=Jin |last11=Liu |first11=Ping |last12=Molderings |first12=Gerhard J. |last13=Rodrigues |first13=Ana Lúcia S. |last14=Satriano |first14=Joseph |last15=Seong |first15=Gong Je |date=2013-09-01 |title=Agmatine: clinical applications after 100 years in translation |url=https://www.sciencedirect.com/science/article/abs/pii/S1359644613001633 |journal=Drug Discovery Today |volume=18 |issue=17 |pages=880–893 |doi=10.1016/j.drudis.2013.05.017 |issn=1359-6446|url-access=subscription }}</ref> 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.<ref>{{Cite web |last1=Satriano |last2=Schwartz |last3=Ishizuka |last4=Lortie |first1=Joseph |first2=Doron |first3=Shunji |first4=Mark |date=September 2001 |title=Suppression of inducible nitric oxide generation by agmatine aldehyde: Beneficial effects in sepsis |url=https://www.researchgate.net/publication/11869978 |website=ResearchGate}}</ref>

==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.<ref name="Piletz_2013">{{cite journal |vauthors=Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, [[Ping Liu|Liu P]], Molderings GJ, Rodrigues AL, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM |date=September 2013 |title=Agmatine: clinical applications after 100 years in translation |journal=Drug Discovery Today |volume=18 |issue=17–18 |pages=880–93 |doi=10.1016/j.drudis.2013.05.017 |pmid=23769988}}</ref> The following outline indicates the categories of control mechanisms, and identifies their molecular targets: 
* [[Neurotransmitter receptor]]s and receptor ionophores. [[Nicotinic acetylcholine receptor|Nicotinic]], [[Imidazoline receptor|imidazoline]] I1 and I2, [[Alpha-2 adrenergic receptor|α2-adrenergic]], glutamate NMDAr, and [[Serotonin receptor|serotonin]] [[5-HT2A receptor|5-HT2A]] and [[5HT-3 receptor|5HT-3]] receptors.
* [[Ion channel]]s. Including: [[ATP-sensitive K+ channel]]s, [[voltage-gated Ca2+ channel|voltage-gated Ca<sup>2+</sup> channels]], and [[acid-sensing ion channel]]s (ASICs).
* [[Membrane transporter]]s. Agmatine specific-selective uptake sites, [[organic cation transporter]]s (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 [[Nitric oxide synthase|NO synthase]] (NOS) isoforms is reported.<ref>{{cite journal|last1=Galea|first1=Elena|last2=Regunathan|first2=S.|last3=Eliopoulos|first3=Vassily|last4=Feinstein|first4=Douglas L.|last5=Reis|first5=Donald J.|date=1996-05-15|title=Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine|journal=Biochemical Journal|language=en|volume=316|issue=1|pages=247–249|doi=10.1042/bj3160247|pmid=8645212|issn=0264-6021|pmc=1217329}}</ref><ref>{{cite journal | vauthors = Gadkari TV, Cortes N, Madrasi K, Tsoukias NM, Joshi MS | title = Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension | journal = Nitric Oxide | volume = 35 | pages = 65–71 | date = November 2013 | pmid = 23994446 | pmc = 3844099 | doi = 10.1016/j.niox.2013.08.005 }}</ref>
* [[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 metalloprotease]]s (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 H<sub>2</sub>O<sub>2</sub> production.<ref>{{cite journal | vauthors = Demady DR, Jianmongkol S, Vuletich JL, Bender AT, Osawa Y | s2cid = 16298942 | title = Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme | journal = Molecular Pharmacology | volume = 59 | issue = 1 | pages = 24–9 | date = January 2001 | pmid = 11125020 | doi = 10.1124/mol.59.1.24 }}</ref>

==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]].<ref name="pmid21564088">{{cite journal | vauthors = Taksande BG, Kotagale NR, Nakhate KT, Mali PD, Kokare DM, Hirani K, Subhedar NK, Chopde CT, Ugale RR | title = Agmatine in the hypothalamic paraventricular nucleus stimulates feeding in rats: involvement of neuropeptide Y | journal = British Journal of Pharmacology | volume = 164 | issue = 2b | pages = 704–18 | date = September 2011 | pmid = 21564088 | pmc = 3188911 | doi = 10.1111/j.1476-5381.2011.01484.x }}</ref> However, supplementation in rat drinking water results in slight reductions in water intake, body weight, and blood pressure.<ref name="pmid24140462">{{cite journal | vauthors = Gilad GM, Gilad VH | title = Evidence for oral agmatine sulfate safety--a 95-day high dosage pilot study with rats | journal = Food and Chemical Toxicology | volume = 62 | pages = 758–62 | date = December 2013 | pmid = 24140462 | doi = 10.1016/j.fct.2013.10.005 }}</ref> In addition, force feeding with agmatine leads to a reduction in body weight gain during rat development.<ref name="pmid24523404">{{cite journal | vauthors = Nissim I, Horyn O, Daikhin Y, Chen P, Li C, Wehrli SL, Nissim I, Yudkoff M | title = The molecular and metabolic influence of long term agmatine consumption | journal = The Journal of Biological Chemistry | volume = 289 | issue = 14 | pages = 9710–29 | date = April 2014 | pmid = 24523404 | pmc = 3975019 | doi = 10.1074/jbc.M113.544726 | doi-access = free }}</ref> It is also found that many fermented foods contain agmatine.<ref>{{cite journal | vauthors = Galgano F, Caruso M, Condelli N, Favati F | title = Focused review: agmatine in fermented foods | journal = Frontiers in Microbiology | volume = 3 | pages = 199 | date = 2012-06-07 | pmid = 22701114 | pmc = 3369198 | doi = 10.3389/fmicb.2012.00199 | doi-access = free }}</ref><ref name="Wang, Che-Chuan 2010">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.</ref>

==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.<ref name="pmid18832451">{{cite journal | vauthors = Haenisch B, von Kügelgen I, Bönisch H, Göthert M, Sauerbruch T, Schepke M, Marklein G, Höfling K, Schröder D, Molderings GJ | title = Regulatory mechanisms underlying agmatine homeostasis in humans | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 295 | issue = 5 | pages = G1104-10 | date = November 2008 | pmid = 18832451 | doi = 10.1152/ajpgi.90374.2008 }}</ref> Rapid elimination from non-brain organs of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours.<ref name="pmid20586417">{{cite journal | vauthors = Huisman H, Wynveen P, Nichkova M, Kellermann G | title = Novel ELISAs for screening of the biogenic amines GABA, glycine, beta-phenylethylamine, agmatine, and taurine using one derivatization procedure of whole urine samples | journal = Analytical Chemistry | volume = 82 | issue = 15 | pages = 6526–33 | date = August 2010 | pmid = 20586417 | doi = 10.1021/ac100858u }}</ref>

== Research ==
A number of potential medical uses for agmatine have been suggested.<ref>{{cite journal | vauthors = Halaris A, Plietz J | title = Agmatine : metabolic pathway and spectrum of activity in brain | journal = CNS Drugs | volume = 21 | issue = 11 | pages = 885–900 | date = 2007 | pmid = 17927294 | doi = 10.2165/00023210-200721110-00002 }}</ref>

Agmatine is also used as a prototrophy selection marker in Microbiology for the study of Sulfolobus and Thermococcus genus.<ref>{{cite journal |last1=Santangelo |first1=Thomas J. |last2=Čuboňová |first2=L'ubomíra |last3=Reeve |first3=John N. |title=Thermococcus kodakarensis Genetics: TK1827-Encoded β-Glycosidase, New Positive-Selection Protocol, and Targeted and Repetitive Deletion Technology |journal=Applied and Environmental Microbiology |date=15 February 2010 |volume=76 |issue=4 |pages=1044–1052 |doi=10.1128/AEM.02497-09|pmc=2820962 }}</ref><ref>{{cite journal |last1=Zhang |first1=Changyi |last2=Cooper |first2=Tara E. |last3=Krause |first3=David J. |last4=Whitaker |first4=Rachel J. |title=Augmenting the Genetic Toolbox for Sulfolobus islandicus with a Stringent Positive Selectable Marker for Agmatine Prototrophy |journal=Applied and Environmental Microbiology |date=15 September 2013 |volume=79 |issue=18 |pages=5539–5549 |doi=10.1128/AEM.01608-13|pmc=3754178 }}</ref>
=== 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 receptor]]s subtypes, norepinephrine release and NO production.<ref name="pmid11454649">{{cite journal | vauthors = Raasch W, Schäfer U, Chun J, Dominiak P | title = Biological significance of agmatine, an endogenous ligand at imidazoline binding sites | journal = British Journal of Pharmacology | volume = 133 | issue = 6 | pages = 755–80 | date = July 2001 | pmid = 11454649 | pmc = 1572857 | doi = 10.1038/sj.bjp.0704153 }}</ref>

=== Glucose regulation ===
Agmatine hypoglycemic effects are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.<ref name="Piletz_2013" />

=== Kidney functions ===
Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.<ref name="pmid15290337">{{cite journal | vauthors = Satriano J | title = Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article | journal = Amino Acids | volume = 26 | issue = 4 | pages = 321–9 | date = July 2004 | pmid = 15290337 | doi = 10.1007/s00726-004-0078-4 | s2cid = 23116711 }}</ref>

=== Neurotransmission ===
Agmatine has been discussed as a putative [[neurotransmitter]]. It is synthesized in the brain, stored in [[synaptic vesicle]]s, accumulated by uptake, released by membrane depolarization, and inactivated by agmatinase. Agmatine binds to α<sub>2</sub>-[[adrenergic receptor]] and [[imidazoline receptor]] binding sites, and blocks [[NMDA receptor]]s and other [[cation]] [[Ionotropic receptor|ligand-gated channels]]. However, while agmatine binds to α<sub>2</sub>-adrenergic receptors, it exerts neither an agonistic nor antagonistic effect on these receptors, lacking any intrinsic activity.<ref>{{cite journal|last1=Pinthong|first1=D.|last2=Wright|first2=I. K.|last3=Hanmer|first3=C.|last4=Millns|first4=P.|last5=Mason|first5=R.|last6=Kendall|first6=D. A.|last7=Wilson|first7=V. G.|date=January 1995|title=Agmatine recognizes alpha 2-adrenoceptor binding sites but neither activates nor inhibits alpha 2-adrenoceptors|journal=Naunyn-Schmiedeberg's Archives of Pharmacology|volume=351|issue=1|pages=10–16|doi=10.1007/BF00169058|issn=0028-1298|pmid=7715734|s2cid=20785398}}</ref><ref>{{cite journal|last1=Pineda|first1=J.|last2=Ruiz-Ortega|first2=J. A.|last3=Martín-Ruiz|first3=R.|last4=Ugedo|first4=L.|date=1996-11-22|title=Agmatine does not have activity at alpha 2-adrenoceptors which modulate the firing rate of locus coeruleus neurones: an electrophysiological study in rat|journal=Neuroscience Letters|volume=219|issue=2|pages=103–106|doi=10.1016/s0304-3940(96)13180-3|issn=0304-3940|pmid=8971790|s2cid=32456961}}</ref> 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.<ref name="Piletz_2013" /> 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.<ref name="Marc_1999">{{cite journal | vauthors = Marc RE | title = Mapping glutamatergic drive in the vertebrate retina with a channel-permeant organic cation | journal = The Journal of Comparative Neurology | volume = 407 | issue = 1 | pages = 47–64 | date = April 1999 | pmid = 10213187 | doi = 10.1002/(sici)1096-9861(19990428)407:1<47::aid-cne4>3.0.co;2-0 | s2cid = 15955446 }}</ref> 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.<ref name="pmid12852826">{{cite journal | vauthors = Su RB, Li J, Qin BY | title = A biphasic opioid function modulator: agmatine | journal = Acta Pharmacologica Sinica | volume = 24 | issue = 7 | pages = 631–6 | date = July 2003 | pmid = 12852826 | url = http://www.chinaphar.com/article/view/9162/9833 }}</ref>

== See also ==
* [[Agmatine deiminase]]
* [[Agmatinase]]

== References ==
{{reflist}}

== Further reading ==
* {{cite journal |doi=10.1016/j.jpain.2004.02.041 |title=Central sensitization: The endogenous NMDA antagonist and NOS inhibitor agmatine inhibits spinal long term potentiation (LTP) |year=2004 |last1=Wilcox |first1=G. |last2=Fiska |first2=A. |last3=Haugan |first3=F. |last4=Svendsen |first4=F. |last5=Rygh |first5=L. |last6=Tjolsen |first6=A. |last7=Hole |first7=K. |journal=The Journal of Pain |volume=5 |issue=3 |pages=S19|doi-access=free }}

{{Neurotransmitters}}
{{Amino acid metabolism intermediates}}
{{Cholinergics}}
{{Glutamatergics}}
{{Imidazolinergics}}

[[Category:Amines]]
[[Category:Guanidines]]
[[Category:Metabolism]]
[[Category:Imidazoline agonists]]
[[Category:Neurotransmitters]]
[[Category:NMDA receptor antagonists]]