Journal article

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

Tracy M Josephs, Andrew N Keller, Elham Khajehali, Aaron DeBono, Christopher J Langmead, Arthur D Conigrave, Capuano Ben, Irina Kufareva, Karen J Gregory, Katie Leach

BRITISH JOURNAL OF PHARMACOLOGY | WILEY | Published : 2020

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 R..

View full abstract

University of Melbourne Researchers

Grants

Awarded by National Institute of General Medical Sciences


Awarded by National Institute of Allergy and Infectious Diseases


Awarded by National Institute of Health General Medical Sciences


Awarded by Australian Research Council


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Funding Acknowledgements

National Institute of General Medical Sciences, Grant/Award Number: GM117424; National Institute of Allergy and Infectious Diseases, Grant/Award Number: AI118985; National Institute of Health General Medical Sciences, Grant/Award Number: GM117424; Australian Research Council, Grant/Award Number: DP170104228; National Health and Medical Research Council of Australia (NHMRC), Grant/Award Numbers: APP1085143, APP1138891