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.
A library of potent
and highly A
3
AR selective pyrimidine-based
compounds was designed to explore non-orthosteric interactions within
this receptor. Starting from a prototypical orthosteric A
3
AR antagonist (ISVY130), the structure-based design explored functionalized
residues at the exocyclic amide L1 region and aimed to provide additional
interactions outside the A
3
AR orthosteric site. The novel
ligands were assembled through an efficient and succinct synthetic
approach, resulting in compounds that retain the A
3
AR potent
and selective profile while improving the solubility of the original
scaffold. The experimentally demonstrated tolerability of the L1 region
to structural functionalization was further assessed by molecular
dynamics simulations, giving hints of the non-orthosteric interactions
explored by these series. The results pave the way to explore newly
functionalized A
3
AR ligands, including covalent drugs and
molecular probes for diagnostic and delivery purposes.
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