CALCIMIMETICS WITH POTENT AND SELECTIVE ACTIVITY ON THE PARATHYROID CALCIUM RECEPTOR

Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca2 + receptor that detects small changes in the level of plasma Ca2+, Bec ause this G protein coupled receptor conceivably provides a distinct m olecular target for drugs useful in treating bone and mineral-related disorders,,ve sought to design small organic molecules that act on the Ca2+ receptor, We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS R-467, increas ed the concentration of cytoplasmic Ca2+ ([Ca2+](i)) in bovine parathy roid cells and inhibited PTH secretion at nanomolar concentrations. Th ese Effects were stereoselective and the R enantiomers were 10- to 100 -fold more potent than the S enantiomers, NPS R-568 potentiated the ef fects of extracellular Ca2+ on [Ca2+](i) and PTH secretion hut was wit hout effect in the absence of extracellular Ca2+, Both compounds shift ed the concentration-response curves for extracellular Ca2+ to the lef t, Presumably, these compounds act as positive allosteric modulators t o increase the sensitivity of tile Ca2+ receptor to activation by extr acellular Ca2+, Both NPS R-467 and NPS R-568 increased [Ca2+](i) in HE K 293 cells expressing the human parathyroid Ca2+ receptor but were wi thout effect in wild-type HEK 293 cells, Neither compound affected the cytoplasmic Ca2+ responses elicited by several other G protein couple d receptors in HEK 293 cells or in bovine parathyroid cells, Significa ntly, these compounds did not affect responses elicited by the homolog ous metabotropic glutamate receptors, mGluR1a, mGluR2, or mGluR8. Thes e compounds therefore act selectively on the Ca2+ receptor, Compounds that mimic or potentiate the effects of extracellular Ca2+ at the Ca2 receptor are termed calcimimetics. The discovery of calcimimetic comp ounds with potent and selective activity enables a pharmacological app roach to regulating plasma revers of PTII, Calcimimetic compounds coul d conceivably provide a specific medical therapy for primary hyperpara thyroidism.