title: Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold.
abstract: 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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Michael Worch
authors.initials: MW
authors.lastname: Boesgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Lenea
authors.initials: L
authors.lastname: Nørskov-Lauritsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Inna
authors.initials: I
authors.lastname: Larsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Kuhne
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: David E
authors.initials: DE
authors.lastname: Gloriam
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sejer Pedersen
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003500:Cyclization; D015195:Drug Design; D006054:Goldfish; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007291:Inosine Monophosphate / Q000378:metabolism; D008024:Ligands; D051379:Mice; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C488584:GPRC6A protein, human; D007211:Indoles; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D007291:Inosine Monophosphate; C542223:2-phenylindole