Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures

• We determined CB1 and CB2 receptor affinity of several phytocannabinoids.
• We evaluated cell toxicity of several phytocannabinoids in neuroblastoma cells.
• We evaluated cell toxicity of several phytocannabinoids in murine dopaminergic neurons.
• Toxic effects of phytocannabinoids do not correspond to binding to the CB1 receptor.

Phytocannabinoids are potential candidates for neurodegenerative disease treatment. Nonetheless, the exact mode of action of major phytocannabinoids has to be elucidated, but both, receptor and non-receptor mediated effects are discussed. Focusing on the often presumed structure–affinity-relationship, Ki values of phytocannabinoids cannabidiol (CBD), cannabidivarin (CBDV), cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), THC acid (THCA) and THC to human CB1 and CB2 receptors were detected by using competitive inhibition between radioligand [3H]CP-55,940 and the phytocannabinoids. The resulting Ki values to CB1 range from 23.5 μM (THCA) to 14,711 μM (CBDV), whereas Ki values to CB2 range from 8.5 μM (THCA) to 574.2 μM (CBDV). To study the relationship between binding affinity and effects on neurons, we investigated possible CB1 related cytotoxic properties in murine mesencephalic primary cell cultures and N18TG2 neuroblastoma cell line. Most of the phytocannabinoids did not affect the number of dopaminergic neurons in primary cultures, whereas propidium iodide and resazurin formation assays revealed cytotoxic properties of CBN, CBDV and CBG. However, THC showed positive effects on N18TG2 cell viability at a concentration of 10 μM, whereas CBC and THCA also displayed slightly positive activities. These findings are neither linked to structural characteristics nor to the receptor binding affinity therewith pointing to another mechanism than a receptor mediated one.