Abstract
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.
Highlights
The superfamily of seven transmembrane receptors (7TMR), commonly referred to as G protein-coupled receptors (GPCRs), is the largest target class in the druggable genome.[1]The receptors in this superfamily regulate virtually every aspect of human physiology, and they are sensors of a wide array of extracellular stimuli.[1]
The process by which ligands differentially modulate G-protein-dependent and/or G-protein-independent (β-arrestin) pathways to mediate specific downstream signal transduction routes is a phenomenon known as functional selectivity or biased agonism.[3]
Article ligands, containing three well-defined regions:[43] (1) the primary pharmacophore (PP) [commonly referred to as the left-hand side (LHS) or head group], consisting of a mono- or disubstituted phenyl-piperazine scaffold, (2) the central linker, that is usually variable in length and nature, and (3) the secondary pharmacophore (SP) [commonly referred to as the right-hand side (RHS) or tail group], generally consisting of a heterocyclic core
Summary
The superfamily of seven transmembrane receptors (7TMR), commonly referred to as G protein-coupled receptors (GPCRs), is the largest target class in the druggable genome.[1]. The assembly of the other five subsets (22, 24, 26, 27, and 29) involved the use of polyfunctional reactive substrates and/or the versatility of the Ugi-Deprotect-Cyclize (UDC) strategy.[47,49,50] the feasibility of the selected pathways relies heavily on the latent reactivity of the different functionalized Ugi adducts (21, 23, 25, and 28), which, upon direct cyclization (22, 26, and 27) or removal of the protecting group, undergo an intramolecular cyclization (24 and 29) to furnish the target structures in an efficient transformation that takes place in one pot In this way, compounds 22a−c were obtained by reaction of 16 with methylamine (17a), isocyanides 19a−c, and phenylglyoxal (18b) as the key precursor (Scheme 1). ■ DRD2 is shown for compound 22a (G-protein biased, B) and compound 27a (β-arrestin biased, C)
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