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 beta arrestin2 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.

Automated summary

The design and synthesis of dualsteric/bitopic agents that can interact with both orthosteric and allosteric binding sites presents a novel approach in medicinal chemistry. In this study, we designed and characterized the first CB2R heterobivalent bitopic ligands, which displayed selective targeting of CB2R and functional selectivity for the cAMP signaling pathway. Additionally, the most promising bitopic ligand FD-22a showed anti-inflammatory and antinociceptive activity in in vitro and in vivo models, respectively. Computational studies further confirmed the bitopic nature of these compounds.