Selective Modulation of Parathyroid Calcium Receptor by Potent Calcimimetics

Parathyroid hormone (PTH) secretion is tightly regulated by a cell surface calcium receptor that is sensitive to fluctuations in plasma calcium levels. Given the receptor's role in bone and mineral-related disorders, there is interest in developing small organic molecules that can target this receptor. In this research, specific phenylalkylamine compounds, NPS R-568 and its deschloro derivative NPS R-467, were identified to increase cytoplasmic calcium levels in bovine parathyroid cells and inhibit PTH secretion at nanomolar concentrations. The effects were stereoselective, with the R enantiomers being significantly more potent than the S enantiomers.

NPS R-568 was found to enhance the effects of extracellular calcium on cytoplasmic calcium levels and PTH secretion but had no effect in the absence of extracellular calcium. Both compounds were able to shift the concentration-response curves for extracellular calcium to the left, suggesting they act as positive allosteric modulators, increasing the sensitivity of the calcium receptor to extracellular calcium activation. They also increased cytoplasmic calcium levels in HEK 293 cells expressing the human parathyroid calcium receptor without affecting wild-type HEK 293 cells or other G protein-coupled receptors.

These findings indicate that NPS R-467 and NPS R-568 selectively target the calcium receptor and could represent a new class of compounds known as calcimimetics. The discovery of calcimimetics with potent and selective activity opens up a pharmacological approach to regulating plasma PTH levels, offering a potential medical therapy for primary hyperparathyroidism.