Premium
DIFFERENT EFFECTS OF 3 NEGATIVE ALLOSTERIC MODULATORS OF G‐PROTEIN COUPLED HUMAN Ca2+ RECEPTOR
Author(s) -
Hu Jianxin,
Jiang Jiankang,
Thomas Craig,
Yang Wu,
Jacobson Kenneth A.,
Spiegel Allen M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1119-a
Subject(s) - allosteric regulation , chemistry , allosteric modulator , transmembrane domain , extracellular , receptor , hek 293 cells , mutant , salt bridge , biophysics , pharmacology , biochemistry , biology , gene
The human Ca 2+ receptor (hCaR) plays a central role in the regulation of extracellular Ca 2+ homeostasis. How calcium binding to the extracellular domain leads to activation of the seven‐transmembrane domain (7TM) of the receptor is a major unresolved question. Synthetic allosteric modulators of the hCaR targeting the 7TM not only have therapeutic potential but also offer insights into the mechanism of receptor activation. We reported earlier that residue E 837 in the 7TM of the receptor plays a pivotal role in the action of structurally related positive modulator NPS R‐568 and negative modulator NPS 2143. We speculated that acidic side‐chain of E 837 forms a critical salt bridge with the positively charged amino group centered in these phenylalkylamines. Recently a novel negative modulator, BMS Compound 1, was reported which shows a unique structure with no positively charged central amine. Our results show that Compound 1 remains capable of negative modulation of the E837A mutant. We further synthesized a novel compound, “JKJ 05”, which is structurally related to Compound 1 but carries a positively charged primary amine. We found that JKJ 05 is also a negative modulator of the wild type hCaR, but less potent than Compound 1. However, very interestingly, JKJ 05 increases calcium response by E837A mutant CaR. These results suggest that the binding pockets of the 3 negative modulators in the hCaR 7TM may partially overlap.