Novel fluorinated cannabinoid analogs modulate cytokine expression in human C20 microglial cells.

Abstract

Phytochemicals derived from the plant Cannabis sativa hold promise in terms of medicinal value. Cannabinoids such as Δ9-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 (F3CBN), the racemic cis-deoxy-trifluoro-THC (F3THC), 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 10µM. Notably, F3CBN and F3THC 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.