Nemeth E F, Steffey M E, Fox J
NPS Pharmaceuticals, Salt Lake City, Utah 84108, USA.
Pediatr Nephrol. 1996 Jun;10(3):275-9. doi: 10.1007/BF00866757.
Parathyroid cells, C-cells, and certain cells in the kidney express a cell surface calcium (Ca2+) receptor which enables these cells to detect and respond to changes in the concentration of extracellular Ca2+. This receptor protein is a member of the G protein-coupled receptor superfamily and shares limited sequence homology only with metabotropic glutamate receptors. The Ca2+ receptor is the primary physiological mechanism regulating the secretion of parathyroid hormone (PTH) and plays a pivotal role in maintaining systemic Ca2+ homeostasis. Compounds that act as Ca2+ receptor agonists are called calcimimetics because they mimic or potentiate the effects of extracellular Ca2+ on parathyroid cell function. NPS R-568 is a small organic calcimimetic compound that acts as a positive allosteric modulator to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. In normal rats, orally administered NPS R-568 decreases plasma levels of PTH and Ca2+ and, at higher doses, increases plasma levels of calcitonin. The changes in the circulating levels of these two hormones explain the hypocalcemia caused by this compound. NPS R-568 also effectively lowers plasma PTH levels in normal humans and in rat models of secondary hyperparathyroidism. Calcimimetic compounds that target the Ca2+ receptor provide a novel therapeutic approach for treating primary and secondary hyperparathyroidism.
甲状旁腺细胞、C细胞以及肾脏中的某些细胞表达一种细胞表面钙（Ca2+）受体，该受体使这些细胞能够检测并响应细胞外Ca2+浓度的变化。这种受体蛋白是G蛋白偶联受体超家族的成员，仅与代谢型谷氨酸受体具有有限的序列同源性。Ca2+受体是调节甲状旁腺激素（PTH）分泌的主要生理机制，在维持全身Ca2+稳态中起关键作用。作为Ca2+受体激动剂的化合物被称为拟钙剂，因为它们模拟或增强细胞外Ca2+对甲状旁腺细胞功能的影响。NPS R-568是一种小的有机拟钙剂化合物，作为正性变构调节剂，可增加Ca2+受体对细胞外Ca2+激活的敏感性。在正常大鼠中，口服NPS R-568可降低血浆中PTH和Ca2+的水平，在较高剂量时，可增加血浆降钙素水平。这两种激素循环水平的变化解释了该化合物引起的低钙血症。NPS R-568在正常人和继发性甲状旁腺功能亢进大鼠模型中也能有效降低血浆PTH水平。靶向Ca2+受体的拟钙剂化合物为治疗原发性和继发性甲状旁腺功能亢进提供了一种新的治疗方法。
