Semi-Synthesis of Dimeric Cannabidiol Derivatives and Evaluation of their Affinity at Neurological Targets

Cannabidiol (CBD) is a natural product associated with a wide range of biological and therapeutic activities. Despite the widespread cultural acceptance of CBD as a medicinal agent, much remains to be determined regarding its precise mechanism(s) of action in treating multiple conditions. CBD has been shown to promiscuously interact with several neurological targets with varying affinities. To expand the chemical space of phytocannabinoids and develop novel chemical compounds, we have designed and synthesized a series of CBD and Δ⁸-THC homodimers, and CBD/Δ⁸-THC heterodimers. The capacity of the dimers to interact with a panel of CNS targets was explored along with the capacity to activate CB1 receptors, as measured by a GIRK channel activation assay. In the panel screen, the dimers were shown to be generally more active toward 5-HT2B and sigma 2 receptors with a range of K_i values from 0.6 to 8.7 μM. These findings provide early evidence that this new class of dimers can serve as novel chemical entities to explore receptor function and the potential for these dimers to have bivalent, bitopic, or dual mechanisms of action.