PT - JOURNAL ARTICLE AU - Lance G. Hammerland AU - James E. Garrett AU - Benjamin C. P. Hung AU - Cynthia Levinthal AU - Edward F. Nemeth TI - Allosteric Activation of the Ca<sup>2+</sup> Receptor Expressed in <em>Xenopus laevis</em> Oocytes by NPS 467 or NPS 568 DP - 1998 Jun 01 TA - Molecular Pharmacology PG - 1083--1088 VI - 53 IP - 6 4099 - http://molpharm.aspetjournals.org/content/53/6/1083.short 4100 - http://molpharm.aspetjournals.org/content/53/6/1083.full SO - Mol Pharmacol1998 Jun 01; 53 AB - 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 &gt; 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. The American Society for Pharmacology and Experimental Therapeutics