Negative allosteric modulators of the human calcium-sensing receptor bind to overlapping and distinct sites within the 7-transmembrane domain.

ABSTRACT:

Background and purpose

Negative allosteric modulators (NAMs) that target the calcium-sensing receptor (CaS receptor) were originally developed for the treatment of osteoporosis by stimulating the release of endogenous parathyroid hormone, but failed in human clinical trials. Several chemically and structurally distinct NAM scaffolds have been described, but it is not known how these different scaffolds interact with the CaS receptor to inhibit receptor signalling in response to agonists.

Experimental approach

In the present study, we used a mutagenesis approach combined with analytical pharmacology and computational modelling to probe the binding sites of four distinct NAM scaffolds.

Key results

Although all four scaffolds bind to the 7-transmembrane and/or extracellu

SUBMITTER: Josephs TM 

PROVIDER: S-EPMC7070164 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature