Davis Randall L, Grotjahn Sascha, Koenig Burkhard, Buck Daniel J, Weaver Jimmie D
Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 W. 17th Street, Tulsa, OK, 74107, USA.
Institut für Organische Chemie, Universität Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany.
Pharmacol Rep. 2025 Feb;77(1):295-301. doi: 10.1007/s43440-024-00680-8. Epub 2024 Nov 29.
Phytochemicals derived from the plant Cannabis sativa hold promise in terms of medicinal value. Cannabinoids such as Δ-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are arguably the best characterized and known to possess wide-ranging therapeutic benefits. The mechanism of action for these therapeutic effects remains to be fully elucidated, however, the anti-inflammatory actions are of particular interest. Maximizing therapeutic effects while limiting adverse effects is crucial in pharmaceutical development. Fluorination of natural products often yields molecules with enhanced biological properties and provides opportunities for intellectual property protection not available to the natural product.
Herein, we describe four novel cannabinoids (a deoxy trifluoroCBN analog (FCBN), the racemic cis-deoxy-trifluoro-THC (FTHC), and truncated pyridine analogs of an intermediate in route to the THC and CBN, SG126 and SG154. Importantly, we provide the initial assessment of the biologic activity of these molecules, by investigating the in vitro effects on metabolic activity (via 3-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide, MTT assay) and cytokine expression (via enzyme linked immunosorbent assay, ELISA) in human C20 microglial cells.
The cannabinoids examined had minimal to no effect on metabolic activity up to 10 µM. Notably, FCBN and FTHC potentiated interleukin-1 β (IL-1β)-induced expression of interferon-γ inducible protein 10 (CXCL10) and IL-6 expression whereas, SG126 and SG154 were inhibitory.
These findings are foundational for new lines of investigation into the therapeutic potential of four novel fluorinated cannabinoids.
源自植物大麻的植物化学物质具有药用价值。诸如Δ-四氢大麻酚（THC）、大麻二酚（CBD）和大麻酚（CBN）等大麻素可以说是特征最明确的，并且已知具有广泛的治疗益处。然而，这些治疗作用的作用机制仍有待充分阐明，其中抗炎作用尤其令人关注。在药物开发中，最大化治疗效果同时限制不良反应至关重要。天然产物的氟化通常会产生具有增强生物学特性的分子，并为天然产物所没有的知识产权保护提供机会。
在此，我们描述了四种新型大麻素（一种脱氧三氟CBN类似物（FCBN）、外消旋顺式脱氧三氟THC（FTHC），以及通往THC和CBN的路线中一种中间体的截短吡啶类似物SG126和SG154）。重要的是，我们通过研究这些分子对人C20小胶质细胞代谢活性（通过3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐，MTT法）和细胞因子表达（通过酶联免疫吸附测定，ELISA）的体外作用，对这些分子的生物学活性进行了初步评估。
所检测的大麻素在浓度高达10 μM时对代谢活性影响极小或无影响。值得注意的是，FCBN和FTHC增强了白细胞介素-1β（IL-1β）诱导的干扰素-γ诱导蛋白10（CXCL10）表达和IL-6表达，而SG126和SG154具有抑制作用。
这些发现为对四种新型氟化大麻素治疗潜力的新研究方向奠定了基础。
