N-Arachidonylglycine

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N-Arachidonylglycine
Names
IUPAC name
N-[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyl]glycine
Systematic IUPAC name
[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenamido]acetic acid
Other names
N-Arachidonylglycine
Arachidonoyl glycine
NA-glycine
Identifiers
3D model (
JSmol
)
7652004
ChEBI
ChEMBL
ChemSpider
MeSH Anandamide
UNII
  • Key: LGEQQWMQCRIYKG-DOFZRALJSA-N checkY
  • InChI=1/C22H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)/b7-6-,10-9-,13-12-,16-15-
    Key: YLEARPUNMCCKMP-DOFZRALJSA-N
  • InChI=1S/C22H35NO3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-21(24)23-20-22(25)26/h6-7,9-10,12-13,15-16H,2-5,8,11,14,17-20H2,1H3,(H,23,24)(H,25,26)/b7-6-,10-9-,13-12-,16-15-
  • O=C(NCC(=O)O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
  • O=C(NCC(=O)O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
Properties
C22H35NO3
Molar mass 361.526 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

N-Arachidonylglycine (NAGly) is a

fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels.[7]
NaGly is found throughout the body and research on its explicit functions is ongoing.

Biosynthesis and degradation

The biosynthesis and degradation of NaGly is not completely understood. Using biochemical approaches, two proposed pathways include: 1) enzymatic conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoid

FAAH has been identified as enzymatic regulators of NAGly metabolism in mice.[10][11]

Research

Effects on the nervous system

NAGly has been hypothesized to have a neurophysiological function of pain suppression, supported by evidence that it suppresses formalin-induced pain behavior in rats.

Fruend's complete adjuvant.[13] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly.[14] Other arachidonic acid-amino acid conjugates did not have the same effects and the actions of NaGly were not affected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.[13][14]

NaGly was shown to be endogenous ligand for the G-protein couple receptor GPR92 along with

dorsal root ganglia (DRG), where GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role of NaGly in the sensory nervous system through the activation of GPR92.[15]

Effects on the immune system

NAGly has been the focus of research on the immune system because of its antinociceptive effects and inhibitory action on components of the immune system. Specifically, it significantly inhibited

prostaglandins associated with increases in inflammation and hyperalgesia. In many mammalian tissues that express COX-2, significant levels of NAGly are naturally present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETE-Gly.[17]

Cell migration

NAGly has been hypothesized to induce cell migration in BV-2

endometrial HEC-1B cells.[18] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such as endometriosis
.

Cellular respiration

NAGly powerfully stimulates oxygen consumption in multiple cell lines, including murine C2C12 myoblasts and human HEK293T cells.[19] This respiratory bioactivity of NAGly is by increased uncoupled (state4u) mitochondrial respiration and depends on the presence of fatty acid desaturation.[20] NAGly respiration bioactivity can be also abrogated in the presence of serum albumin, which functions as an NAGly carrier in murine blood plasma.[21]

Other targets

Insulin secretion

NaGly was identified as a novel insulin secretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels.[22] Additionally, this action was dependent on extracellular glucose level.[22]

Additional biochemical interactions

NaGly has been shown to inhibit the glycine transporter GLYT2a in a non-competitive fashion with arachidonic acid and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachidonyl amino acids, especially because other conjugated amino acids had similar effects.[23]

References

  1. PMID 12234618
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  2. PMID 19460156
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  3. PMID 9057852
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  4. PMID 19647113
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  5. ^
    PMID 20346144
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  6. PMID 16844083
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  7. PMID 26875980
    .
  8. PMID 19460156
    .
  9. PMID 19013794
    .
  10. PMID 29967167
    .
  11. PMID 32271712
    .
  12. ^
    PMID 11518719
    .
  13. ^
    PMID 17727733
    .
  14. ^
    S2CID 35178601
    .
  15. ^
    PMID 18499677
    .
  16. ^ WO application 9738688, Ferrante A, Poulos A, Pitt M, Easton C, Sleigh M, Rathjen D, Widmer F, "Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids", published 23 October 1997, assigned to Peptide Technology Pty Ltd. and Women's and Children's Hospital Adelaide 
  17. PMID 12176025
    .
  18. PMID 21595653
    .
  19. PMID 27374330
    .
  20. PMID 29533650
    .
  21. PMID 32402239
    .
  22. ^
    PMID 15967412
    .
  23. PMID 16899062
    .
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