Detalle de: 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 DRD 2 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 DRD 2 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 DRD 2 crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profile.