Cannabinoids as Context-Dependent Modulators of the Adenosine A3 Receptors: Potential Orthosteric and Allosteric Mechanisms.

Serrano-Marín J.; Navarro G.; de Medina V.; Ferreiro-Vera C.; Lillo J.; Franco R. · Pharmacological research · 2026

**Background & Methods** This review examined whether cannabidiol (CBD) and cannabigerol (CBG) modulate human adenosine A3 receptor (A3R) signaling using in vitro cAMP assays, molecular docking, binding-energy calculations, and molecular dynamics simulations. The study evaluated cannabinoid effects alone and in combination with adenosine in A3R-expressing cells, with specificity confirmed using selective receptor antagonists. **Key Findings** - Both CBD and CBG inhibited forskolin-stimulated cAMP accumulation in A3R-expressing cells with A3R-specific activity (blocked by PSB-10 antagonist but not A2A antagonist SCH 58261), with CBG demonstrating superior potency (IC50 = 0.130 µM vs. CBD = 1.05 µM) despite comparable maximal inhibitory responses. - CBG functioned as an adenosine potency enhancer: 100 nM CBG reduced adenosine's apparent IC50 from 138 nM to 1.0 nM (approximately 138-fold increase in potency) and increased maximal inhibitory response, while 100 nM CBD showed more modest enhancement (138 nM to 42 nM). - Molecular modeling suggests CBG stabilizes an occupancy-dependent secondary receptor pose that fine-tunes orthosteric agonist-receptor interactions, supporting a context-dependent allosteric modulation mechanism rather than direct competitive antagonism. **Dosage & Administration** Not reported. Study utilized in vitro concentrations ranging from nanomolar to micromolar ranges (100 nM CBD/CBG; adenosine concentrations from 1.0-138 nM). **Safety & Adverse Effects** Not reported. This preclinical mechanistic study did not assess clinical safety or adverse effects. **Evidence Quality** This is a review article based on in vitro experimental data with significant limitations. Findings are restricted to cell-based assays and computational models; no animal studies, clinical trials, or direct binding assays were conducted. The proposed allosteric mechanism requires validation through additional studies including direct binding kinetics, proximity assays, comprehensive receptor-subtype profiling, and structural analyses. Adenosine A3R remains understudied despite therapeutic potential, limiting contextual understanding of findings. The context-dependent modulatory effects observed suggest cannabinoid-adenosine interactions are complex and may vary by tissue type and physiologic conditions—factors not fully explored here. Results cannot yet be extrapolated to in vivo conditions or clinical applications.

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