Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold

G protein-coupled receptors (GPCRs)
represent a biological target
class of fundamental importance in drug therapy. The GPRC6A receptor
is a newly deorphanized class C GPCR that we recently reported for
the first allosteric antagonists based on the 2-arylindole privileged
structure scaffold (e.g., 1–3). Herein,
we present the first structure–activity relationship study
for the 2-arylindole antagonist 3, comprising the design,
synthesis, and pharmacological evaluation of a focused library of
3-substituted 2-arylindoles. In a FRET-based inositol monophosphate
(IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor
in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor
over
related GPCRs, making 7 and 34b the most
potent and selective antagonists for the GPRC6A receptor reported
to date.