title: Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568.
abstract: The Ca2+ receptor is a G protein-coupled receptor that enables parathyroid cells and certain other cells in the body to respond to changes in the concentration of extracellular Ca2+. In this study, two novel phenylalkylamine compounds, NPS 467 and NPS 568, were examined for effects on Xenopus laevis oocytes expressing the bovine or human parathyroid Ca2+ receptors. Increases in chloride current (ICl) were elicited in oocytes expressing the bovine Ca2+ receptor when the extracellular Ca2+ concentration was raised above 1.5 mM, whereas Ca2+ concentrations > 3 mM were generally necessary to elicit responses in oocytes expressing the human Ca2+ receptor. NPS 467 and NPS 568 potentiated the activation of ICl by extracellular Ca2+ in oocytes expressing either Ca2+ receptor homolog, and this resulted in a leftward shift of the Ca2+ concentration-response curve. Neither compound was active in the absence of extracellular Ca2+. Certain inorganic and organic cations known to activate the Ca2+ receptor were substituted for elevated levels of extracellular Ca2+ to increase ICl and the effects of these agonists were also potentiated by NPS 568 or NPS 467. The effects of NPS 568 were stereoselective and the R-enantiomer was about 10-fold more potent than the corresponding S-enantiomer. Neither NPS 467 nor 568 affected ICl in water-injected oocytes or in oocytes expressing the substance K receptor or the metabotropic glutamate receptor 1a. These results provide compelling evidence that NPS 467 and NPS 568 act directly upon the parathyroid Ca2+ receptor to increase its sensitivity to activation by extracellular Ca2+. This activity suggests that these compounds are positive allosteric modulators of the Ca2+ receptor. As such, these compounds define a new class of pharmacological agents with potent and selective actions on the Ca2+ receptor.
authors.affiliation: NPS Pharmaceuticals, Inc., Salt Lake City, Utah 84108, USA. lhammerland@npsp.com
authors.forename: L G
authors.initials: LG
authors.lastname: Hammerland
authors.forename: J E
authors.initials: JE
authors.lastname: Garrett
authors.forename: B C
authors.initials: BC
authors.lastname: Hung
authors.forename: C
authors.initials: C
authors.lastname: Levinthal
authors.forename: E F
authors.initials: EF
authors.lastname: Nemeth
mesh_terms: D000494:Allosteric Regulation; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000187:drug effects*; D002417:Cattle; D018118:Chloride Channels / Q000502:physiology; D005260:Female; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D010627:Phenethylamines; D011437:Propylamines; D011994:Recombinant Proteins / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D000814:Aniline Compounds; D002135:Calcium-Binding Proteins; D018118:Chloride Channels; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; C111654:NPS R-467; D010627:Phenethylamines; D011437:Propylamines; D011994:Recombinant Proteins; D002118:Calcium