Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity
| Autor: | Lars Grundemar, Christophe Mallet, Ludivine Boudieu, Anders Blomgren, Johan L. Å. Nilsson, Anders Blomqvist, Peter M. Zygmunt, Ulf J. Nilsson, Kiseko Shionoya, Anders Sundin, Alain Eschalier |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Models Molecular Metabolite Pharmacology Aminophenols 01 natural sciences chemistry.chemical_compound Transient Receptor Potential Channels Fatty acid amide hydrolase Drug Discovery Pain Measurement Analgesics 0303 health sciences biology digestive oral and skin physiology Brain General Medicine Farmakologi och toxikologi Liver AM404 Female lipids (amino acids peptides and proteins) psychological phenomena and processes medicine.drug Antipyretics Indazoles Analgesic TRPV1 Pain TRPV Cation Channels Arachidonic Acids Pharmacology and Toxicology Amidohydrolases Structure-Activity Relationship 03 medical and health sciences medicine Animals Humans Antipyretic Rats Wistar Acetaminophen 030304 developmental biology 010405 organic chemistry Organic Chemistry 0104 chemical sciences Mice Inbred C57BL nervous system chemistry Prostaglandin-Endoperoxide Synthases biology.protein Cyclooxygenase Paracetamol TRP channel FAAH Fever |
| Zdroj: | European Journal of Medicinal Chemistry. 213:113042 |
| ISSN: | 0223-5234 |
| Popis: | 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. (C) 2020 The Author(s). Published by Elsevier Masson SAS. Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR) |
| Databáze: | OpenAIRE |
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