RT Journal Article
SR Electronic
T1 Upacicalcet Is a Novel Secondary Hyperparathyroidism Drug that Targets the Amino Acid Binding Site of Calcium-Sensing Receptor 
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 183
OP 195
DO 10.1124/molpharm.122.000522
VO 102
IS 4
A1 Hirofumi Sato
A1 Sei Murakami
A1 Yusuke Horii
A1 Go Nishimura
A1 Ryosuke Iwai
A1 Moritaka Goto
A1 Naoki Takahashi
YR 2022
UL http://molpharm.aspetjournals.org/content/102/4/183.abstract
AB The human calcium-sensing receptor (CaSR) is a G protein-coupled receptor that maintains extracellular Ca2+ homeostasis by regulating the secretion of parathyroid hormone. Upacicalcet is a novel positive allosteric modulator of CaSR that is used for the treatment of secondary hyperparathyroidism. In the present study, to clarify the binding site of upacicalcet to CaSR, we conducted binding studies and agonistic activity studies in HEK-293T cells expressing human CaSR (intact and mutant) and an in silico docking-simulation analysis. As a result, upacicalcet competed with L-tryptophan and was thought to affect the amino acid binding site. In addition, the effects of substitutions at the amino acid binding site on the binding abilities to upacicalcet as well as the effects on receptor function as measured using inositol-1 monophosphate accumulation were examined. Upacicalcet interacted with several CaSR residues that constitute the amino acid binding site. Based on these results, we performed an in silico analysis and obtained a binding mode, consistent with the in vitro study results. Our study revealed that upacicalcet is a novel secondary hyperparathyroidism drug that targets the amino acid binding site of CaSR. Upacicalcet is expected to become a new treatment option for secondary hyperparathyroidism because the binding site differs from that of conventional drugs; consequently, it may be effective for patients who are not sensitive to conventional drugs, and it may have a superior safety profile.SIGNIFICANCE STATEMENT Upacicalcet interacts with several residues that constitute the amino acid binding site of the calcium-sensing receptor (CaSR) and shows a potent positive allosteric activity. This mechanism differs from those of conventional drugs. Therefore, upacicalcet can be regarded as a novel secondary hyperparathyroidism drug that acts on the amino acid binding site of CaSR.