PMID- 19759318
OWN - NLM
STAT- MEDLINE
DCOM- 20091222
LR  - 20220330
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 331
IP  - 3
DP  - 2009 Dec
TI  - 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.
PG  - 775-86
LID - 10.1124/jpet.109.159228 [doi]
AB  - 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-((1R)-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.
FAU - Lu, Jenny Ying Lin
AU  - Lu JY
AD  - Department of Metabolic Disorders, Amgen San Francisco, South San Francisco, 
      California, USA.
FAU - Yang, Yuhua
AU  - Yang Y
FAU - Gnacadja, Gilles
AU  - Gnacadja G
FAU - Christopoulos, Arthur
AU  - Christopoulos A
FAU - Reagan, Jeff D
AU  - Reagan JD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090916
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Aniline Compounds)
RN  - 0 (CASR protein, human)
RN  - 0 (Inositol Phosphates)
RN  - 0 (N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine)
RN  - 0 (Phenethylamines)
RN  - 0 (Propylamines)
RN  - 0 (Receptors, Calcium-Sensing)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Algorithms
MH  - Allosteric Regulation
MH  - Aniline Compounds/*pharmacology
MH  - Animals
MH  - Calcium/*agonists/metabolism
MH  - Cell Line
MH  - Cricetinae
MH  - Cricetulus
MH  - Humans
MH  - Hypercalcemia/genetics/metabolism
MH  - Hyperparathyroidism/genetics/metabolism
MH  - Inositol Phosphates/metabolism
MH  - *Models, Biological
MH  - *Mutation
MH  - Phenethylamines
MH  - Plasmids
MH  - Propylamines
MH  - Receptors, Calcium-Sensing/*agonists/*genetics
MH  - Transfection
EDAT- 2009/09/18 06:00
MHDA- 2009/12/23 06:00
CRDT- 2009/09/18 06:00
PHST- 2009/09/18 06:00 [entrez]
PHST- 2009/09/18 06:00 [pubmed]
PHST- 2009/12/23 06:00 [medline]
AID - jpet.109.159228 [pii]
AID - 10.1124/jpet.109.159228 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2009 Dec;331(3):775-86. doi: 10.1124/jpet.109.159228. Epub 
      2009 Sep 16.