Effect of the calcimimetic R-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on correcting inactivating mutations in the human calcium-sensing receptor.

[familial hypocalciuric hypercalcemia]

Over 257 mutations in the human calcium-sensing receptor (hCaSR ) gene have been reported . Heterozygous inactivating mutations can result in familial hypocalciuric hypercalcemia (FHH ), whereas homozygous inactivating mutations can cause life-threatening neonatal severe hyperparathyroidism (NSHPT ). Activating mutations in the hCaSR can result in hypercalciuria and hypocalcemia . A recent publication on the successful treatment of a patient suffering from FHH with the hCaSR positive allosteric modulator cinacalcet prompted our interest in exploring the molecular pharmacology of calcimimetics to correct signaling defects associated with inactivating hCaSR mutations . We prepared 11 mutant hCaSRs , previously identified in patients suffering from NSHPT or FHH , and tested their ability to couple to inositol phosphate accumulation and intracellular calcium mobilization in transiently transfected human embryonic kidney 293 and Chines hamster ovary cells using the calcimimetic R-568 [3 -(2 -chlorophenyl )-N-((1 R )-1 -(3 -methoxyphenyl )ethyl )-1 -propanamine ]. We found that extracellular Ca (2 +) was significantly less potent on the mutated receptors compared with wild-type hCaSR . However , R-568 was able to enhance the potency of extracellular Ca (2 +) toward the mutant hCaSRs . Furthermore , R-568 increased the maximal agonist response on several of the mutant CaSRs . We applied a novel operational model of allosteric modulation /agonism that provided a common mechanism to account for the behavior of the wild-type and mutant hCaSRs . The data provide evidence for the potential use of calcimimetics to treat diseases such as FHH and NSHPT where severe hypercalcemia can be life-threatening .