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Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and synthesis of a novel series of CBD-based structural analogues, and the in vivo evaluation of their potential antinociceptive activity. Methods: Using a two-step synthetic route, 26 new terpene-cinnamoyl acyl-hydrazone analogues were obtained and were submitted to in vivo screening in the classical formalin-induced paw edema and hot plate assays. Results: The compounds PQM-292, PQM-293, PQM-295, PQM-307, PQM-308, and PQM-309 exhibited the best results in the neurogenic phase (first phase) of the formalin-induced licking response, showing comparable results to morphine. Notably, in the inflammatory phase (second phase), compound PQM-292 exhibited the best anti-inflammatory activity. Interestingly, in the hot plate model, six other compounds (PQM-274, PQM-291, PQM-294, PQM-304, PQM-305, and PQM-378) showed the best antinociceptive activity in comparison to morphine, especially PQM-274, which exhibited an antinociceptive effect almost equivalent to the reference drug. Interestingly, these findings suggested that these bioactive compounds, despite their structural similarity, act through different mechanisms, which were investigated by molecular docking with CB1, CB2, and TRPV1 receptors. In silico results indicated that the most active compounds should act through different mechanisms, probably involving interactions with TRPA1. Conclusions: Therefore, due to the promising antinociceptive activity observed for these highlighted compounds, particularly for PQM-292 and PQM-274, without apparent toxicity and psychoactive effects, and the possible involvement of diverse mechanisms of action, these compounds could be considered as promising starting points to the development of new drug candidate prototypes of clinical interest.<\/jats:p>","DOI":"10.3390\/ph18050755","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T06:54:28Z","timestamp":1747724068000},"page":"755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, Synthesis, and Evaluation of Antinociceptive Properties of Novel CBD-Based Terpene-Cinnamoyl-Acyl-Hydrazone Analogues"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2723-6385","authenticated-orcid":false,"given":"Mikaela Lucinda","family":"de Souza","sequence":"first","affiliation":[{"name":"PeQuiM-Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo\u00e3o Pedro Barros","family":"de Paiva","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology of Pain and Inflammation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-577, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graziella dos Reis Rosa","family":"Franco","sequence":"additional","affiliation":[{"name":"PeQuiM-Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1674-818X","authenticated-orcid":false,"given":"Vanessa 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Pereira","family":"Lontra","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology of Pain and Inflammation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-577, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo Ara\u00fajo","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology of Pain and Inflammation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-577, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tha\u00eds Biondino Sardella","family":"Giorno","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology of Pain and Inflammation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-577, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella 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Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-992X","authenticated-orcid":false,"given":"Claudio","family":"Viegas Jr.","sequence":"additional","affiliation":[{"name":"PeQuiM-Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, Alfenas 37133-840, MG, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102386","DOI":"10.1016\/j.arr.2024.102386","article-title":"Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits","volume":"100","author":"Jha","year":"2024","journal-title":"Ageing Res. 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