Albane Kessler

N1-Arylsulfonyl-N2-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexanes: A New Class of Calcilytic Agents Acting at the Calcium-Sensing Receptor

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that senses extracellular calcium [Ca]e, thereby maintaining calcium homeostasis in the organism. It belongs to the heptahelical family of receptors, which includes the metabotropic glutamate receptors (mGluR), the B-type g-aminobutyric acid receptor (GABAB-R) as well as certain pheromone and taste receptors. 2] As shown by cloning of its cDNA, the CaSR is present in many tissues, including the brain and the parathyroid gland. At the surface of the latter, the CaSR detects and responds to small changes of circulating [Ca]e, thereby regulating parathyroid hormone (PTH) secretion. There exists a negative feedback relationship between [Ca]e levels and PTH secretion. Thus, high levels of [Ca]e activate the CaSR, thereby inhibiting PTH secretion, whereas low [Ca]e levels diminish CaSR activation, stimulating PTH secretion. These observations led to the hypothesis that compounds that could activate this receptor (CaSR TMagonists∫) should lead to decreased levels of circulating PTH. Such TMagonists∫ could be of therapeutic benefit in diseases such as hyperparathyroidism. Alternatively, compounds that could block the action of the CaSR (CaSR TMantagonists∫) should theoretically lead to increased plasma levels of PTH. Because increased PTH levels are associated with bone formation, CaSR antagonists could provide a novel approach to the treatment of osteoporosis. However, to be clinically useful, such compounds would also have to provide only short-term elevations in PTH levels since chronically high PTH levels are known to lead to bone loss. The first small organic molecules reported to interact specifically and with good affinities with the CaSR were NPS R-467 (1) and NPS R-568 (2, Scheme 1). 11] These compounds were shown to increase the concentration of cytoplasmic calcium ([Ca]i) in bovine parathyroid cells and, most significantly, to inhibit PTH secretion. Since these compounds, referred to