Pharmacological characterization of the anti-nociceptive and anti-inflammatory effects of new CBD-based terpenyl-N-acyl-aryl-hydrazone analogues

Inflammation and nociception are complex biological processes involved in numerous pathological conditions. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid known for its analgesic and anti-inflammatory properties, primarily mediated through TRPV1 modulation and inhibition of pro-inflammatory cytokines. In this study, we investigated a series of eight CBD-based terpene- N -acyl-aryl-hydrazone analogues (PQM-242 to PQM-249) for their antinociceptive and anti-inflammatory activities, especially focused on the characterization of the mechanisms of action underlying their effects. Chemical- and thermal-induced nociception models revealed that PQM-242, PQM-243, and PQM-249 exhibited the most potent central and peripheral antinociceptive effects. In the carrageenan-induced subcutaneous air pouch model, these compounds significantly reduced leukocyte migration, protein extravasation, and production of key pro-inflammatory cytokines (IL-1β, IL-6, TNFα), with PQM-249 showing the strongest inhibition of TNFα. These findings suggest that the compounds act, at least in part, through modulation of TRPV1-mediated pathways and suppression of IL-1β/TNFα signaling, resembling and potentially enhancing the mechanisms observed for CBD. Overall, PQM-242, PQM-243, and PQM-249 emerge as promising candidates for further development as analgesic and anti-inflammatory agents. • Eight new CBD-based Terpenyl- N -Acyl-Aryl-Hydrazones were synthetized. • Antinociceptive and anti-inflammatory activities were evaluated in preclinical models. • PQM-242, PQM-243, and PQM-249 were the most potent compounds. • Significant peripheral and central antinociceptive effects were observed. • Production of pro-inflammatory cytokines (IL-1β, IL-6, TNF) were also inhibited.