New Terpenyl-Cinnamoyl-Hydrazone Analogues of Cannabidiol with Potent Antinociceptive Effect
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Pain is a complex process involving peripheral and central sensitization, neuroinflammation, and altered neurotransmission. Current analgesics often have limited efficacy and undesirable side effects, underscoring the need for safer and more effective options. Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis sativa, has shown promise as an analgesic through modulation of multiple pathways. In this study, novel terpenyl-cinnamoyl-hydrazone analogs were synthesized and evaluated for antinociceptive potential in preclinical nociception models. The compounds were tested in chemical (formalin-induced licking) and thermal (hot plate) assays in mice. Mechanistic studies employed naloxone (opioid antagonist), atropine (muscarinic antagonist), AM251 (CB1 antagonist), yohimbine (α2-adrenergic antagonist), and ondansetron (5-HT3 antagonist). Most compounds displayed antinociceptive activity, with PQM-274, PQM-291, and PQM-294 showing greater effects than CBD. Naloxone and AM251 reversed the effects of these three compounds. Atropine abolished PQM-291’s effect, and ondansetron inhibited PQM-290’s activity, whereas yohimbine produced no change. This study reports, for the first time, the antinociceptive properties of terpenyl-cinnamyl-N-acyl-hydrazones with structural features inspired by CBD, suggesting their potential as novel multitarget analgesic candidates.
