Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands

The design of dualsteric/bitopic agents as single chemical entities
able to simultaneously interact with both the orthosteric and an allosteric
binding site represents a novel approach in medicinal chemistry. Biased
dualsteric/bitopic agents could enhance certain signaling pathways
while diminishing the others that cause unwanted side effects. We
have designed, synthesized, and functionally characterized the first
CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric
compound, our bitopic ligands selectively target CB2R versus CB1R
and show a functional selectivity for the cAMP signaling pathway versus
βarrestin2 recruitment. Moreover, the most promising bitopic
ligand FD-22a displayed anti-inflammatory activity in
a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain.
Finally, computational studies clarified the binding mode of these
compounds inside the CB2R, further confirming their bitopic nature.