One for the Price of Two…Are Bivalent Ligands Targeting Cannabinoid Receptor Dimers Capable of Simultaneously Binding to both Receptors?

Bivalent ligands bridging two G-protein-coupled receptors (GPCRs) provide valuable pharmacological tools to target oligomers. The success of therapeutically targeting the cannabinoid CB1 receptor has been limited, in part due to its widespread neuronal distribution. Therefore, CB1 ligands targeting oligomers that exhibit restricted distribution or altered pharmacology are highly desirable, and several bivalent ligands containing a CB1 pharmacophore have been reported. Bivalent ligand action presumes that the ligand simultaneously binds to both receptors within the dimeric complex. However, based on the current understanding of CB1 ligand binding, existing bivalent ligands are too short to bind both receptors simultaneously. However, ligands with longer linkers may not be the solution, because evidence suggests that ligands enter CB1 through the lipid bilayer and, thus, linkers are unlikely to exit the receptor through its external face. Thus, the entire premise of designing bivalent ligands targeting CB1 must be revisited.

TrendsGPCRs represent the largest family of membrane proteins involved in cellular signal transduction.GPCRs are involved in diverse physiological processes and provide valuable drug targets for numerous diseases.GPCRs are now generally accepted to form dimers or larger oligomeric complexes, but the functional role of receptor association is unclear in most cases.Targeting of specific heteromers holds promise for enabling activation of subsets of receptors, resulting in greater specificity of therapeutic effect.One approach utilised to target receptor dimers is the development of bivalent ligands, which comprise two pharmacophores linked by a spacer, with the goal of simultaneous activation of both receptors with higher affinity than they target either constituent receptor on its own.