Abstract
Despite the discovery of many ions and molecules that activate the Ca2+ receptor, there are no known ligands that block this receptor. Reported here are the pharmacodynamic properties of a small molecule, NPS 2143, which acts as an antagonist at the Ca2+receptor. This compound blocked (IC50 of 43 nM) increases in cytoplasmic Ca2+ concentrations [Ca2+]i elicited by activating the Ca2+ receptor in HEK 293 cells expressing the human Ca2+ receptor. NPS 2143, even when tested at much higher concentrations (3 μM), did not affect the activity of a number of other G protein-coupled receptors, including those most structurally homologous to the Ca2+ receptor. NPS 2143 stimulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC50 of 41 nM) over a range of extracellular Ca2+ concentrations and reversed the effects of the calcimimetic compound NPS R-467 on [Ca2+]iand on secretion of PTH. When infused intravenously in normal rats, NPS 2143 caused a rapid and large increase in plasma levels of PTH. Ca2+ receptor antagonists are termed calcilytics and NPS 2143 is the first substance (either atomic or molecular) shown to possess such activity. The pharmacodynamic properties of NPS 2143 together with the recently demonstrated effects of this compound on bone formation support the view that orally active calcilytic compounds might provide a novel anabolic therapy for osteoporosis.
Footnotes
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↵1 In additional studies to be reported elsewhere, it was found that these high concentrations of NPS 2143 were also without effect on either group II (mGluR2 or 3) and group III (mGluR8) receptors.
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↵2 The compound does, however, have other activities. Testing in cross-screening binding assays against approximately 50 G protein-coupled receptors, nine enzymes and three ion channels showed that NPS 2143 possesses some affinity for adrenergic, serotoninergic, histaminergic, and dopaminergic receptor subtypes, as well as a sodium channel.
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Parts of this work were presented at the Second Joint Meeting of the American Society for Bone and Mineral Research and the International Bone and Mineral Society, San Francisco, CA, December 1–6, 1998, and appeared in an abstract [(1998) Bone23 (Suppl):S156].
- Abbreviations:
- PTH
- parathyroid hormone
- [Ca2+]i
- cytoplasmic Ca2+concentration
- mGluR
- metabotropic glutamate receptor
- GABABR
- γ-aminobutyric acid type B receptor
- HEK
- human embryonic kidney
- Received March 27, 2001.
- Accepted May 29, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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