Projects per year
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 extracellular or intracellular loops, they occupy distinct regions, as previously shown for positive allosteric modulators of the CaS receptor. Furthermore, different NAM scaffolds mediate negative allosteric modulation via distinct amino acid networks. Conclusion and Implications: These findings aid our understanding of how different NAMs bind to and inhibit the CaS receptor. Elucidation of allosteric binding sites in the CaS receptor has implications for the discovery of novel allosteric modulators.
Original language | English |
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Pages (from-to) | 1917-1930 |
Number of pages | 14 |
Journal | British Journal of Pharmacology |
Volume | 177 |
Issue number | 8 |
DOIs | |
Publication status | Published - Apr 2020 |
Projects
- 3 Finished
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Towards the rational design of calcium sensing receptor allosteric modulators for the treatment of osteoporosis and calcium handling disorders
Leach, K., Gregory, K., Conigrave, A., Capuano, B., Kufareva, I., Thakker, R. & Hannan, F. M.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/21
Project: Research
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Stabilising biased allosteric G protein-coupled receptor conformations
Leach, K., Gregory, K., Capuano, B. & Kufareva, I.
Australian Research Council (ARC), Monash University, University of California System
1/01/17 → 31/12/19
Project: Research
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Engendering biased signalling at the human calcium sensing receptor (CaSR) to correct pathophysiology
Leach, K., Conigrave, A. & Mason, R.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/18
Project: Research