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.