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Xasodfuih/Sandbox
Clinical data
Other namesN-(4-hydroxyphenyl)-arachidonamide
N-arachidonoylphenolamine
4-hydroxyphenyl arachidonamide
Legal status
Legal status
Identifiers
  • (5Z,8Z,11Z,14Z)- N-(4-hydroxyphenyl) icosa- 5,8,11,14- tetraenamide
JSmol)
SMILES
  • Oc1ccc(NC(=O)CCC/C=C\\C/C=C\\C/C=C\\C/C=C\\CCCCC)cc1

AM404 also known as N-arachidonoylphenolamine is an active metabolite of paracetamol (acetaminophen) responsible for all or part of its analgesic action.[1]

History

Together with a number of other

structure-activity relationship of related compounds. The study determined however that AM404 exhibits only a weak affinity for both types of cannabinoid receptors—an order of magnitude less than anandamide.[2]

The importance of AM404 was first observed in an article that appeared in the journal

carrier-mediated transport
is pharmacological inhibition,

antonio calignano

researchers from the

University of Naples and the University of Connecticut, were looking to identify inhibitors of the putative anandamide transport (AMT). Amongst the compounds they tested, AM404 turned out to be the strongest inhibitor. In vitro, a concentration of anandamide that was well below the threshold when applied alone produced an almost maximal effect when applied together with AM404. In mice, intravenous coadministration of AM404 and anandamide significantly increased the analgesic effect of the latter in the hot plate test.[3]

A more extensive report comparing the inhibitory effect of AM404 with 33 other analogues was published in

2-arachidonoylglycerol (2-AG)—another cannabinoid agonist that had been found to be endogenous in 1995.[5]

Simultaneously with these discoveries a parallel line of events took place. After the first

Italian National Research Council) published a paper in Nature suggesting that anandamide
was a strong agonist for VR1. This paper stirred a fair amount of controversy.

A far more striking discovery was made in the same year. A collaboration betwe


[6]

In the same year the group coordinated by

capsaicin receptor.[8]
)

[9]

Relationship with paracetamol

The connection between AM404 and

primary amine, is conjugated with arachidonic acid in the brain and spinal column to form AM404. Mice lacking the fatty acid amide hydrolase cannot metabolize this.[10]

An article that appeared in the journal

knockout mice lacking the CB1 receptor.[11]

Pharmacology

AM404 was originally reported to be an endogenous cannabinoid reuptake inhibitor, preventing the transport of

fatty acid amide hydrolase (FAAH) by AM404 is likely responsible for all of its attributed "reuptake" properties, since intracellular FAAH hydrolysis of anandamide changes the intra/extracellular anandamide equilibrium.[12]

AM404 is also TRPV1 agonist, and also prevents cyclooxygenase COX-1 and COX-2 and prostaglandin synthesis. AM404 is thought to induce its analgesic action through its activity on the cannabinoid, COX and TRPV systems, all of which are present in pain and thermoregulatory pathways.[10]

References

  1. PMID 16438952.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  2. PMID 8893848. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  3. PMID 9262477. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  4. PMID 10318965. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  5. S2CID 23959453. {{cite journal}}: Unknown parameter |month= ignored (help
    )
  6. PMID 10822052. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  7. S2CID 9784858. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  8. S2CID 7970319. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  9. PMID 11277920. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  10. ^
    S2CID 10837155. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link
    )
  11. S2CID 21291734. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link
    )
  12. ^ Glaser, S.T. et al. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4269-74.


Category:Endocannabinoid reuptake inhibitors

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