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

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