Calcimimetics with potent and selective activity on the parathyroid calcium receptor

Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca(2+) receptor that detects small changes in the level of plasma Ca(2+). Because this G protein-coupled receptor conceivably provides a distinct molecular target for drugs useful in treating bone and mineral-related disorders, we sought to design small organic molecules that act on the Ca(2+) receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS R-467, increased the concentration of cytoplasmic Ca(2+) ([Ca(2+)](i)) in bovine parathyroid cells and inhibited PTH secretion at nanomolar concentrations. These effects were stereoselective and the R enantiomers were 10- to 100-fold more potent than the S enantiomers. NPS R-568 potentiated the effects of extracellular Ca(2+) on [Ca(2+)](i) and PTH secretion but was without effect in the absence of extracellular Ca(2+). Both compounds shifted the concentration–response curves for extracellular Ca(2+) to the left. Presumably, these compounds act as positive allosteric modulators to increase the sensitivity of the Ca(2+) receptor to activation by extracellular Ca(2+). Both NPS R-467 and NPS R-568 increased [Ca(2+)](i) in HEK 293 cells expressing the human parathyroid Ca(2+) receptor but were without effect in wild-type HEK 293 cells. Neither compound affected the cytoplasmic Ca(2+) responses elicited by several other G protein-coupled receptors in HEK 293 cells or in bovine parathyroid cells. Significantly, these compounds did not affect responses elicited by the homologous metabotropic glutamate receptors, mGluR1a, mGluR2, or mGluR8. These compounds therefore act selectively on the Ca(2+) receptor. Compounds that mimic or potentiate the effects of extracellular Ca(2+) at the Ca(2+) receptor are termed calcimimetics. The discovery of calcimimetic compounds with potent and selective activity enables a pharmacological approach to regulating plasma levels of PTH. Calcimimetic compounds could conceivably provide a specific medical therapy for primary hyperparathyroidism.