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 Ki 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.