Potent and Subtype-Selective Dopamine D₂ Receptor Biased Partial Agonists Discovered via an Ugi-Based Approach

Using a previously unexplored, efficient, and versatile multicomponent method, we herein report the rapid generation of novel potent and subtype-selective DRD₂ biased partial agonists. This strategy exemplifies the search for diverse and previously unexplored moieties for the secondary/allosteric pharmacophore of the common phenyl-piperazine scaffold. The pharmacological characterization of the new compound series led to the identification of several ligands with excellent DRD₂ affinity and subtype selectivity and remarkable functional selectivity for either the cAMP (22a and 24d) or the β-arrestin (27a and 29c) signaling pathways. These results were further interpreted on the basis of molecular models of these ligands in complex with the recent DRD₂ crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profile.