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Calcimimetics with potent and selective activity on the parathyroid calcium receptor
E F Nemeth1, M E Steffey, L G Hammerland
1NPS Pharmaceuticals, Inc., 420 Chipeta Way, Salt Lake City, UT 84108, USA. enemeth@npsp.com
Summary
Researchers discovered novel calcimimetic compounds that selectively modulate the calcium-sensing receptor, offering a new therapeutic avenue for parathyroid hormone (PTH) related disorders.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Parathyroid hormone (PTH) secretion is regulated by the calcium-sensing receptor (CaR) on parathyroid cells.
- The CaR detects plasma Ca2+ levels and is a potential drug target for mineral and bone disorders.
Purpose of the Study:
- To design small organic molecules that modulate the Ca2+ receptor.
- To investigate the potential of these molecules as therapeutic agents for PTH-related disorders.
Main Methods:
- Screening of phenylalkylamine compounds for activity on Ca2+ receptor.
- Assays measuring cytoplasmic Ca2+ ([Ca2+]i) and PTH secretion in bovine parathyroid cells and HEK 293 cells.
- Stereoselective analysis and testing for off-target effects on other G protein-coupled receptors.
Main Results:
- Phenylalkylamine compounds NPS R-568 and NPS R-467 increased [Ca2+]i and inhibited PTH secretion at nanomolar concentrations.
- These effects were stereoselective, with R enantiomers being more potent.
- Compounds acted as positive allosteric modulators, increasing Ca2+ receptor sensitivity and showing selectivity for the Ca2+ receptor over other GPCRs.
Conclusions:
- Discovery of potent and selective calcimimetic compounds (NPS R-467, NPS R-568).
- These calcimimetics offer a pharmacological approach to regulate plasma PTH levels.
- Potential therapeutic application for primary hyperparathyroidism and other mineral-related disorders.