Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System*

@article{Hgesttt2005ConversionOA,
  title={Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System*},
  author={Edward D. H{\"o}gest{\"a}tt and Bo A. G. Jönsson and Anna Ermund and David A. Andersson and Henrik Bj{\"o}rk and Jessica P Alexander and Benjamin F. Cravatt and Allan I. Basbaum and Peter M. Zygmunt},
  journal={Journal of Biological Chemistry},
  year={2005},
  volume={280},
  pages={31405 - 31412}
}
Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the… 

Figures and Tables from this paper

Fatty Acid Amide Hydrolase-Dependent Generation of Antinociceptive Drug Metabolites Acting on TRPV1 in the Brain

The findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS and support the suggestion that this drug metabolite contributes to paracetamol’s analgesic activity via activation of bulbospinal pathways.

Fatty Acid Amide Hydrolase-Dependent Generation of Antinociceptive Drug Metabolites Acting on TRPV 1 in the Brain

The findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS and suggest that this drug metabolite contributes to paracetamol’s analgesic activity via activation of bulbospinal pathways.

Acetaminophen: Ancient drug with a novel analgesic mechanism of action

It has been unraveled that paracetamol may exert novel mechanisms of action, likely relevant for their analgesic action, by modulating protein kinase C epsilon (PKCε) and substance P in the peripheral sensory neurons.

Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors.

The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described, and it is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.

Dopamides, Vanillylamides, Ethanolamides, and Arachidonic Acid Amides of Anti‐inflammatory and Analgesic Drug Substances as TRPV1 Ligands

It is found that dopamine amides of fenamic acids have TRPV1 agonist activity in the nanomolar range, and that the arachidonoyl amide of a dipyrone metabolite has TRpV1 antagonist activity.

The paracetamol metabolite N-acetylp-benzoquinone imine reduces excitability in first- and second-order neurons of the pain pathway through actions on KV7 channels

Results show that the paracetamol metabolite NAPQI dampens excitability of first- and second-order neurons of the pain pathway through an action on KV7 channels.

Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action

The purpose of this review was to summarize the previous and new issues related to the analgesic mechanisms of acetaminophen, and it is believed that it will allow clinicians to consider new pain management techniques involvingacetaminophen.

The biosynthesis of N-arachidonoyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine.

...

References

SHOWING 1-10 OF 87 REFERENCES

Mechanism of acetaminophen inhibition of cyclooxygenase isoforms.

Results are consistent with a mechanism of inhibition of acetaminophen in which it acts to reduce the active oxidized form of COX to the resting form, consistent with the known tissue selectivity of acetamine.

Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain*

It is shown that the conjugate of arachidonic acid and glycine (N-arachidonylglycine (NAGly) is present in bovine and rat brain as well as other tissues and that it suppresses tonic inflammatory pain.

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases

The hypothesis that the clinical action of acetaminophen is mediated by inhibition of PGHS activity, and that hydroperoxide concentration contributes to its cellular selectivity, is supported.

Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172.

The results indicate that anandamideinternalization in mouse brain neurons is independent of FAAH activity, and the compound N-(5Z, 8Z, 11Z, 14Z eicosatetraenyl)-4-hydroxybenzamide (AM1172) blocked [(3)H]anandamide internalization in rodent cortical neurons and human astrocytoma cells without acting as a FAAH substrate or inhibitor.

Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors.

Indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation and can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.

Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides

It is shown that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides6–8, and the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats are reported.

Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide.

The potency of ibuprofen as an inhibitor of anandamide metabolism was of the same order of magnitude as required for inhibition of cyclooxygenase-2 in cell-free systems and of the peak plasma concentrations of this drug following a 2 x 200 mg dose regimen.

Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

Results indicate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception, and may represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever.

Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors.

In a simple, intact cell model of both vanilloids- and anandamide-like activity, arvanil was shown to behave as a "hybrid" activator of cannabinoid and vanilloid receptors.
...