Design, Synthesis, and Biological Activity of New {CB}2 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