NPS R-568: a type II calcimimetic compound that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of parathyroid hormone and calcium.
NPS R-568: a type II calcimimetic compound that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of parathyroid hormone and calcium.
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NPS R-568：一种II型拟钙化合物，作用于大鼠甲状旁腺细胞钙受体，降低甲状旁腺激素和钙的血浆水平。
DOI：
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发表时间：
1999
影响因子：
3.5
通讯作者：
E. Nemeth
中科院分区：
文献类型：
--
作者：
J. Fox;S. H. Lowe;B. Petty;E. Nemeth
模拟钙剂如N-（3-[2-氯苯基]丙基）-（R）-α-甲基-3-甲氧基苄胺（CXR-568）在体外增强细胞外Ca（2+）对甲状旁腺Ca（2+）受体的作用并抑制甲状旁腺激素（PTH）分泌。在本研究中，当对正常大鼠灌胃给药时，AXR-568引起PTH水平快速、剂量依赖性（艾德（50），1.1 +/- 0.7 mg/kg）降低，随后血浆Ca（2+）降低（艾德（50），10.4 +/- 3.7 mg/kg）。在较高剂量（>/=3.3 mg/kg）下，PTH在15分钟内降至最低水平，持续时间呈剂量依赖性。剂量为10 - 100 mg/kg时，低钙血症发作迅速（<30分钟），剂量为33 - 100 mg/kg时，持续时间>24小时。低钙反应的幅度和动力学均不受全肾切除术的影响，这表明miR-568不会通过作用于肾Ca（2+）受体增加Ca（2+）排泄而诱导低钙血症。相比之下，甲状旁腺切除术（完整甲状腺）消除了对AXR-568的低钙反应，无论大鼠是低钙还是在给药前通过钙输注急性正常或高钙。这些数据表明，甲状旁腺Ca（2+）受体可以在体内被小分子有机化合物选择性激活，以降低PTH和Ca（2+）的血浆水平，从而确定该化合物在体内的作用机制。此外，这些数据为Ca（2+）受体是调节全身Ca（2+）稳态的主要分子实体的观点提供了药理学支持。
Calcimimetics like N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) potentiate the effects of extracellular Ca(2+) on parathyroid Ca(2+) receptors and inhibit parathyroid hormone (PTH) secretion in vitro. When administered by gavage to normal rats in this study, NPS R-568 caused a rapid, dose-dependent (ED(50), 1.1 +/- 0.7 mg/kg) decrease in PTH levels that was paralleled by a subsequent decrease in plasma Ca(2+) (ED(50), 10.4 +/- 3.7 mg/kg). At higher doses (>/=3.3 mg/kg), PTH was reduced to a minimum level within 15 min, the duration of which was dose dependent. With doses of 10 to 100 mg/kg, the hypocalcemia was rapid in onset (<30 min) and, at 33 to 100 mg/kg, persisted for >24 h. Neither the magnitude nor the kinetics of the hypocalcemic response was affected by total nephrectomy, demonstrating that NPS R-568 does not induce hypocalcemia by acting on renal Ca(2+) receptors to increase Ca(2+) excretion. In contrast, parathyroidectomy (intact thyroid) abolished the hypocalcemic response to NPS R-568, regardless of whether the rats were hypocalcemic or rendered acutely normo- or hypercalcemic by calcium infusion before dosing. These data show that the parathyroid Ca(2+) receptor can be selectively activated in vivo with a small organic compound to decrease plasma levels of PTH and Ca(2+) and thus define the mechanism of action of this compound in vivo. Moreover, the data add pharmacological support to the view that the Ca(2+) receptor is the primary molecular entity regulating systemic Ca(2+) homeostasis.
DOI：
10.1152/ajprenal.1996.271.4.f951
发表时间：
1996-10-01
影响因子：
4.2
作者：
Riccardi, D;Lee, WS;Hebert, SC
通讯作者：
Hebert, SC
DOI：
10.1073/pnas.92.1.131
发表时间：
1995-01-03
影响因子：
11.1
作者：
RICCARDI, D;PARK, J;HEBERT, SC
通讯作者：
HEBERT, SC
钙离子感应障碍。
DOI：
10.1210/jcem.81.6.8964824
发表时间：
1996
期刊：
The Journal of clinical endocrinology and metabolism.
影响因子：
--
作者：
Pearce,SH;Brown,EM
通讯作者：
Brown,EM