A Boron-Containing Analogue of Acetaminophen Induces Analgesic Effect in Hot Plate Test and Limited Hepatotoxicity

Abstract

Acetaminophen is the most sold drug to treat pain. The TRPV1 channel is among its main targets. Due to its over-the-counter availability, its use is known as the main cause of acute liver failure induced by drugs. In addition, boron-containing compounds (BCC) have shown higher efficiency, potency, and affinity than their carbon counterparts. The present study explored the potential analgesic effect and hepatotoxicity of a BCC with a similar chemical structure to acetaminophen. Docking studies were carried out on the TRPV1 channel. In addition, a hot plate test was carried out with three doses of acetaminophen (APAP) and equimolar doses of 4-acetamidophenylboronic acid (4APB) in C57bl/6 mice. These same mice were submitted to a partial hepatectomy and continued compound administration, then they were sacrificed at day seven of treatment to analyze the liver histology and blood chemistry markers. From the in silico assays, it was observed that APAP and 4APB shared interactions with key residues, but 4APB showed a higher affinity on the orthosteric site. Mice administered with 4APB showed a higher latency time than those administered with their equimolar dose of APAP and the control group, with no motor pathway affected. The 4APB groups did not show an increase in hepatic enzyme activity while the APAP did show an increase in activity that was dose-dependent. Although all the experimental groups did show necrosis and inflammation, all APAP groups showed a greater cellular damage than their 4APB counterparts. In addition, the LD50 of 4APB is 409 mg/kg (against APAP-LD50 of 338 mg/kg). Thus, in the current evaluation, 4APB was a better analgesic and safer than APAP.

Keywords

• acetaminophen
• boron
• pain
• analgesia
• TRPV
• hepatotoxicity