For this reason further characterization of the

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]). For this reason, further characterization of the different tissue-specific response of CaSR in the parathyroids and bone cells to different ligands may help to design and/or employ molecules whose binding to the receptor is known or expected to be linked to a specific downstream signaling pathway. Despite the fact that calcimimetics were developed soon after the cloning of the CaSR and calcilytics afterward, once the skeletal benefits of an intermittent PTH administration became evident, for the purpose of this review, the skeletal effects of calcilytics on bone will be discussed first. Calcilytics: effects on bone Simultaneous with the interest in developing molecules able to activate the CaSR, researchers were also interested in es- tablishing molecules able to inhibit it, which were termed calcilytics. NPS 2143 was the first calcilytic compound to be developed, and it shifts the concentration-response curve of extracellular calcium to the right, without changing the max- imal response [ 86 ]. The stimulation of PTH by means of calcilytics was exploited to reproduce a significant but transient increase in serum PTH in order to stimulate bone anabolism [ 83 ]. Indeed, subcutaneous administration of parathyroid hormone, avail- able as a fragment of 34-amino acid PTH(1 34) and as the full-length peptide, intact PTH(1 84), constitutes therapeutic treatments for osteoporosis since they are able to increase bone formation [ 87 ]. However, both PTH1 34) and PTH1 84) induce an excessive bone remodeling and carry the B black box ^ label of a 2-year prescription because of the long-term risk of osteosarcoma in preclinical studies in rats. When com- pared to the administration of PTH(1 34) or PTH(1 84), calcilytic drugs present advantages, namely, the ability to be orally bioavailable and modulate secretion of endogenous PTH, which ensures that PTH serum levels do not increase beyond the physiological range [ 88 ]. Thus, the main desirable characteristics present in calcilytic compounds are the ability to transiently increase PTH secretion, in order to obtain the anabolic effects of the hormone and lead to bone formation, drug specificity to the CaSR, and oral administration. NPS 2143 was the first calcilytic compound to be devel- oped by NPS Pharmaceuticals, Inc., together with formerly SmithKline Beecham (now GlaxoSmithKline). NPS 2143 was produced upon structural modification of the SB- 222338 compound, a molecule presenting low specificity and potency. NPS 2143 presented encouraging results in in vitro studies in bovine parathyroid cells, as well as in in vivo studies in rats. However, oral administration of NPS 2143 to the ovariectomized rat, a model of osteoporosis, did not lead to an increase in bone formation, which was attributed to the long half-life of the compound, which led to an increase of long duration in PTH levels (>4 h). Nevertheless, the results obtained with NPS 2143 in the ovariectomized rat allowed proof of the possibility of designing a molecule that antago- nizes the CaSR and leads to transient increases in plasma PTH
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  • Fall '18
  • Andrea Cupp
  • resorbing bone, CASR

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