Design, synthesis, and biological profiling of fluorinated cannabidiol and cannabigerol derivatives as promising therapeutic agents

作者：Ferenc Dániel Petróczi, Angéla Tótik, Miklós Bege, József Király, Erzsébet Szabó, Zsuzsanna Szabó, Nikoletta Dobos, Rasha Ghanem Kattoub, Charu Upadhyay, Eszter Ostorházi, Jan Hodek, Jan Weber, József Arany, Dorottya Ádám, Christos C. Zouboulis, Attila Oláh, István Bajza, Árpád Tósaki, Gábor Halmos, Brijesh Rathi, Pál Herczegh, Anikó Borbás, Ilona Bereczki · 发表于：Journal of Cannabis Research · 年份：2026 · DOI：10.1186/s42238-026-00403-1 · 被引用次数：1 · 研究领域：Cannabis and Cannabinoid Research、Psychedelics and Drug Studies、Pharmacological Receptor Mechanisms and Effects

BACKGROUND: Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic phytocannabinoids that have significant, broad-spectrum therapeutic potential in a variety of pharmacological areas, but their unfavorable pharmacokinetics, such as extensive first-pass metabolism and low bioavailability, hinder their effective medical applications. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical properties. Incorporation of fluorine atom(s) at appropriate positions often improves the metabolic stability of the parent compound, increasing its bioavailability, and enhances its binding affinity to therapeutic targets, making fluorine a highly valuable element in modern drug development. Furthermore, amino functional groups may improve the water solubility and bioavailability of the compounds. Building on these principles, our strategy focused on introducing groups containing mono-, di-, and trifluoroethylamine or fluorinated aniline moieties into cannabinoids to improve their pharmacokinetic and pharmacological profiles. METHODS: Mannich-type reaction was applied, using commercially available 2-fluoroethylamine, 2,2-difluoroethylamine, 2,2,2-trifluoroethylamine, 3-fluoroaniline and 4-fluoroaniline as reagents. One or two oxazine rings with fluorine-containing side chains were condensed to the aromatic core of the cannabinoids, and the formation of mono- or disubstituted derivatives was controlled by the appropriate choice of reactio...