Agmatine

Last updated
Agmatine
Agmatine.svg
Names
IUPAC name
1-(4-Aminobutyl)guanidine [1]
Identifiers
3D model (JSmol)
3DMet
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.626 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 206-187-7
KEGG
MeSH Agmatine
PubChem CID
UNII
  • InChI=1S/C5H14N4/c6-3-1-2-4-9-5(7)8/h1-4,6H2,(H4,7,8,9) Yes check.svgY
    Key: QYPPJABKJHAVHS-UHFFFAOYSA-N Yes check.svgY
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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 Wikipedia-Agmatine Metabolic Pathways.jpg
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:

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

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Arginine</span> Amino acid

Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the amino and guanidino groups are protonated, resulting in a cation. Only the l-arginine (symbol Arg or R) enantiomer is found naturally. Arg residues are common components of proteins. It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG. The guanidine group in arginine is the precursor for the biosynthesis of nitric oxide. Like all amino acids, it is a white, water-soluble solid.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

<span class="mw-page-title-main">Spermidine</span> Chemical compound

Spermidine is a polyamine compound found in ribosomes and living tissues and having various metabolic functions within organisms. It was originally isolated from semen.

Gasotransmitters is a class of neurotransmitters. The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria. Currently, only nitric oxide, carbon monoxide, and hydrogen sulfide are accepted as gasotransmitters. According to in vitro models, gasotransmitters, like other gaseous signaling molecules, may bind to gasoreceptors and trigger signaling in the cells.

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

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<i>N</i>-Acetylserotonin Chemical compound

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It also has biological activity in its own right, including acting as a melatonin receptor agonist, an agonist of the TrkB, and having antioxidant effects.

<span class="mw-page-title-main">Alpha-adrenergic agonist</span> Class of drugs

Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction.

<span class="mw-page-title-main">Cannabinoid receptor 1</span> Mammalian protein found in Homo sapiens

Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endocannabinoids, a group of retrograde neurotransmitters that include anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).

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<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

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References

  1. ↑ "agmatine (CHEBI:17431)". Chemical Entities of Biological Interest. UK: European Bioinformatics Institute. 15 August 2008. Main. Retrieved 11 January 2012.
  2. ↑ Kossel A (1910). "Über das Agmatin". Zeitschrift für Physiologische Chemie (in German). 66 (3): 257–261. doi:10.1515/bchm2.1910.66.3.257.
  3. ↑ "agmantine" . Oxford English Dictionary (Online ed.). Oxford University Press.(Subscription or participating institution membership required.)
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. 1 2 3 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  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. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ Su RB, Li J, Qin BY (July 2003). "A biphasic opioid function modulator: agmatine". Acta Pharmacologica Sinica. 24 (7): 631–6. PMID   12852826.

Further reading