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Vol. 53, Issue 6, 1083-1088, June 1998
NPS Pharmaceuticals, Inc., Salt Lake City, Utah 84108
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.
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