Abstract
G protein-coupled receptors (GPCRs) are the most common targets of drug action. Allosteric modulators bind to the seven-transmembrane domain of family 3 GPCRs and offer enhanced selectivity over orthosteric ligands that bind to the large extracellular N terminus. We characterize a novel negative allosteric modulator of the human Ca(2+) receptor, Compound 1, that retains activity against the E837A mutant that lacks a response to previously described positive and negative modulators. A related compound, JKJ05, acts as a negative allosteric modulator on the wild type receptor but as a positive modulator on the E837A mutant receptor. This positive modulation critically depends on the primary amine in JKJ05, which appears to interact with acidic residue Glu(767) in our model of the seven-transmembrane domain of the receptor. Our results suggest the need for identification of possible genetic variation in the allosteric site of therapeutically targeted GPCRs.
Highlights
3 of the GPCR2 superfamily has recently become a focus for the discovery of new allosteric modulators with therapeutic potential [1]
These results indicate that residue Glu837, which is crucial for allosteric modulation by phenylalkylamines, is not crucial for allosteric modulation by Compound 1
3 of the G protein-coupled receptors (GPCRs) superfamily has recently become a focus for the discovery of new allosteric modulators with therapeutic potential
Summary
3 of the GPCR2 superfamily has recently become a focus for the discovery of new allosteric modulators with therapeutic potential [1]. This positive modulation critically depends on the primary amine in JKJ05, which appears to interact with acidic residue Glu767 in our model of the seven-transmembrane domain of the receptor.
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