AM404

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AM404
Identifiers
  • (5Z,8Z,11Z,14Z)- N-(4-Hydroxyphenyl)icosa- 5,8,11,14-tetraenamide
JSmol)
SMILES
  • O=C(Nc1ccc(O)cc1)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
  • InChI=1S/C26H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-26(29)27-24-20-22-25(28)23-21-24/h6-7,9-10,12-13,15-16,20-23,28H,2-5,8,11,14,17-19H2,1H3,(H,27,29)/b7-6-,10-9-,13-12-,16-15- checkY
  • Key:IJBZOOZRAXHERC-DOFZRALJSA-N checkY
 ☒NcheckY (what is this?)  (verify)

AM404, also known as N-arachidonoylphenolamine,

AM cannabinoids discovered by Alexandros Makriyannis
and his team.

Pharmacokinetics

AM404 is found in the brains of animals and

4-aminophenol by the action of FAAH.[5][6]

It is also generated in vitro from 4-aminophenol by peripheral sensory neurons.[7]

Pharmacodynamics

AM404 is a weak agonist of cannabinoid receptors

CB2, an inhibitor of endocannabinoid transporter, a potent activator of TRPV1,[5] and a very potent inhibitor of Nav1.8 and 1.7.[7] It weakly inhibits cyclooxygenases (COX).[8] The endocannbinoid system, TRPV1, COX are involved in pain and thermoregulatory pathways.[8] Nav1.8 and 1.7 are involved in peripheral pain perception.[7]

CB1 and CB2

AM404 is a weak agonist of cannabinoid receptors

CB2.[5]

Endocannabinoid concentration

It is established that AM404 increases concentrations of the endogenous cannabinoid anandamide within the synaptic cleft, contributing to its analgesic activity.[8] This has been well characterised as involving endocannabinoid transporter inhibition, but the precise transporter responsible is yet to be determined.[8][9][10]

AM404 was originally reported to be an

knockout mice has found that brain cells internalize anandamide through a selective transport mechanism which is independent of FAAH activity.[9]
It is this mechanism which is inhibited by AM404.

TRPV1

AM404 is also a TRPV1 agonist[11] and inhibitor of cyclooxygenase COX-1 and COX-2, thus attenuating prostaglandin synthesis.

The anticonvulsant action of AM404 is mediated through TRPV1, according to Suemaru et al. (2018),

CB1 receptors.[4]

Sodium channels

AM404 has also been reported to inhibit

1.7 channels at nanomolar concentrations in vitro.[7] AM404 injected into the hind paw of rats increase the pain threshold for the treated paw, but not the untreated paw, confirming the peripheral nature of this effect. It also lowers pain responses in a few other in vivo models when injected directly into the affected area. Other tested metabolites of paracetamol do not block pain-sensing sodium channels in vitro.[13]

See also

References

  1. S2CID 245483361
    .
  2. PMID 22172309
    .
  3. PMID 16438952
    .
  4. ^
    PMID 21037491
    .
  5. ^
    PMID 26921661
    .
  6. PMID 29238213
    .
  7. ^
    PMID 40465624
    .
  8. ^
    S2CID 10837155
    .
  9. ^
    PMID 15138300
    .
  10. ^
    PMID 12655057
    .
  11. PMID 10822052
    .
  12. S2CID 51652230
    .
  13. ^ "Does Paracetamol Block Peripheral Pain?". Conexiant. 11 June 2025.
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