Nemeth E F, Steffey M E, Hammerland L G, Hung B C, Van Wagenen B C, DelMar E G, Balandrin M F
NPS Pharmaceuticals, Inc., 420 Chipeta Way, Salt Lake City, UT 84108, USA.
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4040-5. doi: 10.1073/pnas.95.7.4040.
Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca2+ receptor that detects small changes in the level of plasma Ca2+. 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 Ca2+ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS R-467, increased the concentration of cytoplasmic Ca2+ ([Ca2+]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 Ca2+ on [Ca2+]i and PTH secretion but was without effect in the absence of extracellular Ca2+. Both compounds shifted the concentration-response curves for extracellular Ca2+ to the left. Presumably, these compounds act as positive allosteric modulators to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. Both NPS R-467 and NPS R-568 increased [Ca2+]i in HEK 293 cells expressing the human parathyroid Ca2+ receptor but were without effect in wild-type HEK 293 cells. Neither compound affected the cytoplasmic Ca2+ 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 Ca2+ receptor. Compounds that mimic or potentiate the effects of extracellular Ca2+ at the Ca2+ 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.
甲状旁腺激素（PTH）的分泌受一种细胞表面钙受体调节，该受体可检测血浆钙水平的微小变化。由于这种G蛋白偶联受体理论上为治疗骨和矿物质相关疾病的药物提供了一个独特的分子靶点，我们试图设计作用于钙受体的有机小分子。我们发现某些苯烷基胺化合物，以NPS R - 568及其去氯衍生物NPS R - 467为代表，可增加牛甲状旁腺细胞中细胞质钙（[Ca2+]i）的浓度，并在纳摩尔浓度下抑制PTH分泌。这些效应具有立体选择性，R型对映体的效力比S型对映体强10至100倍。NPS R - 568增强了细胞外钙对[Ca2+]i和PTH分泌的作用，但在无细胞外钙的情况下无作用。两种化合物都使细胞外钙的浓度 - 反应曲线向左移动。据推测，这些化合物作为正变构调节剂，增加钙受体对细胞外钙激活的敏感性。NPS R - 467和NPS R - 568都能增加表达人甲状旁腺钙受体的HEK 293细胞中的[Ca2+]i，但对野生型HEK 293细胞无作用。这两种化合物都不影响HEK 293细胞或牛甲状旁腺细胞中其他几种G蛋白偶联受体引发的细胞质钙反应。值得注意的是，这些化合物不影响同源代谢型谷氨酸受体mGluR1a、mGluR2或mGluR8引发的反应。因此，这些化合物选择性地作用于钙受体。在钙受体处模拟或增强细胞外钙作用的化合物被称为拟钙剂。具有强效和选择性活性的拟钙剂的发现为调节PTH的血浆水平提供了一种药理学方法。拟钙剂理论上可为原发性甲状旁腺功能亢进提供一种特异性医学疗法。
