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Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity

Nilsson, Johan LU ; Mallet, Christophe ; Shionoya, Kiseko ; Blomgren, Anders LU ; Sundin, Anders P. LU ; Grundemar, Lars LU ; Boudieu, Ludivine ; Blomqvist, Anders ; Eschalier, Alain and Nilsson, Ulf J. LU , et al. (2021) In European Journal of Medicinal Chemistry 213.
Abstract

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and... (More)

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Acetaminophen, Analgesic, FAAH, Fever, Pain, Paracetamol, TRP channel, TRPV1
in
European Journal of Medicinal Chemistry
volume
213
article number
113042
publisher
Elsevier Masson SAS
external identifiers
  • pmid:33257173
  • scopus:85097102900
ISSN
0223-5234
DOI
10.1016/j.ejmech.2020.113042
language
English
LU publication?
yes
id
d3cc82cb-5385-430e-ae51-f3dac5c1af30
date added to LUP
2021-01-11 16:52:31
date last changed
2024-09-20 12:57:22
@article{d3cc82cb-5385-430e-ae51-f3dac5c1af30,
  abstract     = {{<p>Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio.</p>}},
  author       = {{Nilsson, Johan and Mallet, Christophe and Shionoya, Kiseko and Blomgren, Anders and Sundin, Anders P. and Grundemar, Lars and Boudieu, Ludivine and Blomqvist, Anders and Eschalier, Alain and Nilsson, Ulf J. and Zygmunt, Peter M.}},
  issn         = {{0223-5234}},
  keywords     = {{Acetaminophen; Analgesic; FAAH; Fever; Pain; Paracetamol; TRP channel; TRPV1}},
  language     = {{eng}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{European Journal of Medicinal Chemistry}},
  title        = {{Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2020.113042}},
  doi          = {{10.1016/j.ejmech.2020.113042}},
  volume       = {{213}},
  year         = {{2021}},
}