New terpenyl–cinnamoyl–hydrazone analogues of cannabidiol with potent antinociceptive effect

Abstract

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 receptor antagonist), atropine (muscarinic receptor antagonist), AM251 (CB1 receptor antagonist), yohimbine (α2-adrenergic receptor antagonist), and ondansetron (5-HT₃ receptor antagonist). Most compounds displayed antinociceptive activity, with PQM-274, PQM-291, and PQM-294 showing greater effects than cannabidiol (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.