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 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.text goes here.Association for the Study of Pain revised its conceptual framework in 2020, highlighting that the experience of pain is not strictly dependent on identifiable tissue injury and is shaped by individual perception and sociocultural context, with important consequences for clinical evaluation and therapeutic planning. 1 Nociception results from multiple inputs, including peripheral signal transduction, spinal transmission through ascending pathways, modulatory mechanisms, and cortical integration. These stages are subject to changes that may be either adaptive or pathological. In chronic pain states, alterations within the central nervous system can lead to a persistent amplification of sensory signaling, a phenomenon commonly referred to as central sensitization. [1][2][3] Endogenous pain control depends on inhibitory systems that regulates nociceptive transmission at spinal and supraspinal levels, and the descending modulatory pathways adjust spinal neuron excitability. A circuit connecting the periaqueductal gray to the rostroventromedial medulla, integrating cortical, limbic, and brainstem inputs exert bidirectional control over nociceptive processing. Depending on physiological and pathological conditions, this system may either suppress or facilitate pain, reflecting its functional heterogeneity. 3 Descending modulation is mediated through several neurotransmitter systems. The opioids constitute a major inhibitory mechanism, acting through μ, δ, and κ receptors to regulate nociceptive signaling. Evidence indicates that persistent pain states and prolonged opioid exposure can induce substantial remodelling a.