RT Journal Article
SR Electronic
T1 A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 348
OP 356
DO 10.1124/mol.116.107276
VO 91
IS 4
A1 De Min, Anna
A1 Matera, Carlo
A1 Bock, Andreas
A1 Holze, Janine
A1 Kloeckner, Jessica
A1 Muth, Mathias
A1 Traenkle, Christian
A1 De Amici, Marco
A1 Kenakin, Terry
A1 Holzgrabe, Ulrike
A1 Dallanoce, Clelia
A1 Kostenis, Evi
A1 Mohr, Klaus
A1 Schrage, Ramona
YR 2017
UL http://molpharm.aspetjournals.org/content/91/4/348.abstract
AB Protean agonists are of great pharmacological interest as their behavior may change in magnitude and direction depending on the constitutive activity of a receptor. Yet, this intriguing phenomenon has been poorly described and understood, due to the lack of stable experimental systems and design strategies. In this study, we overcome both limitations: First, we demonstrate that modulation of the ionic strength in a defined experimental set-up allows for analysis of G protein–coupled receptor activation in the absence and presence of a specific amount of spontaneous receptor activity using the muscarinic M2 acetylcholine receptor as a model. Second, we employ this assay system to show that a dualsteric design principle, that is, molecular probes, carrying two pharmacophores to simultaneously adopt orthosteric and allosteric topography within a G protein–coupled receptor, may represent a novel approach to achieve protean agonism. We pinpoint three molecular requirements within dualsteric compounds that elicit protean agonism at the muscarinic M2 acetylcholine receptor. Using radioligand-binding and functional assays, we posit that dynamic ligand binding may be the mechanism underlying protean agonism of dualsteric ligands. Our findings provide both new mechanistic insights into the still enigmatic phenomenon of protean agonism and a rationale for the design of such compounds for a G protein–coupled receptor.