Calcimimetics with potent and selective activity on the parathyroid calcium receptor

Abstract

Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca 2؉ receptor that detects small changes in the level of plasma Ca 2؉ . Because this G protein-coupled receptor conceivably provides a distinct molecular target for drugs useful in treating bone and mineral-related disorders, we sought to design small organic molecules that act on the Ca 2؉ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS receptor are termed calcimimetics. The discovery of calcimimetic compounds with potent and selective activity enables a pharmacological approach to regulating plasma levels of PTH. Calcimimetic compounds could conceivably provide a specific medical therapy for primary hyperparathyroidism.The concentration of ionized calcium (Ca 2ϩ ) in plasma is regulated largely by parathyroid hormone (PTH), which acts on the kidney and on bone to increase the level of plasma Ca The Ca 2ϩ receptor is a member of the G protein-coupled receptor superfamily and possesses an unusually large extracellular domain, the characteristic seven transmembrane domain, and a relatively long cytoplasmic tail. In these topological aspects, the Ca 2ϩ receptor is similar to metabotropic glutamate receptors (mGluR), although the sequence homology between these receptors is only about 25%. The human (1,078 amino acids) and bovine (1,085 amino acids) parathyroid cell Ca 2ϩ receptors are glycosylated proteins of ϳ120 kDa and are 93% identical (5). The Ca 2ϩ receptor expressed on authentic parathyroid cells or in heterologous cellular systems couples to phospholipase C and, when activated by increased concentrations of extracellular Ca 2ϩ , elicits rapid increases in inositol 1,4,5-trisphosphate and [Ca 2ϩ ] i (2, 4, 6). Thus, in its functional and structural properties, the parathyroid Ca 2ϩ receptor is akin to other cell surface receptors that initially transduce extracellular signals into functional cellular responses. The difference is that the physiological ligand for the Ca 2ϩ receptor is an inorganic ion, rather than an organic molecule.G protein-coupled receptors have been a classic site of action for drugs useful in treating various diseases. As a member of the G protein-coupled receptor superfamily, the Ca 2ϩ receptor is seemingly an ideal target for new pharmaceuticals useful in treating disorders of bone and mineral metabolism, such as hyperparathyroidism and osteoporosis. At present, however, the only ligands known to act on the Ca 2ϩ receptor are other inorganic di-and trivalent cations (2, 7) and organic polycations (8-10) that are nonselective and lack utility as systematic therapeutics. The present report describes the results of our initial efforts to devise a small organic compound that selectively acts on the parathyroid Ca 2ϩ receptor yet lacks a polycationic structure. NPS R-467 and NPS R-568 (Fig. 1) are two compounds that emerged from this effort. They are potent and selective activators of the Ca 2ϩ receptor and inhibit PTH secretion in vitro....

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

“…In addition, calcimimetic compounds were used to reduce serum PTH levels in mice. Calcimimetics are small organic compounds that, upon binding to the CaSR, enhance the sensitivity of the CaSR for Ca 2+ in an allosteric fashion, thereby inhibiting PTH secretion by the parathyroid glands, and may provide a novel therapy for treating hyperparathyroidism (Nemeth 1996;Nemeth et al 1998). Infusion of these calcimimetic compounds in normal mice resulted in decreased serum PTH levels, serum Ca 2+ levels and renal expression of TRPV5 as well as reduced expression of TRPV6 in duodenum (van Abel et al, unpublished data).…”

Cinacalcet HCl, an Oral Calcimimetic Agent for the Treatment of Secondary Hyperparathyroidism in Hemodialysis and Peritoneal Dialysis

“…The calcium-sensing receptor located on the surface of chief cells in the parathyroid gland is the principal regulator of PTH secretion and therefore is an ideal target for therapies to treat secondary HPT (15)(16)(17). Calcimimetics are positive allosteric modulators of the calcium-sensing receptor that increase its sensitivity to extracellular calcium by lowering the threshold for activation by extracellular calcium ions (16 -18).…”

Comment moduler l’activité du récepteur du calcium extracellulaire ?

“…La phénylalkylamine NPS R-568 et le composé indolique Calindol, appartenant à deux familles chimiques différentes, sont considérées comme des calcimimétiques de classe II (Figure 3). Ces molé-cules organiques de faible poids moléculaire présentent une affinité comparable pour le CaR (~0,1 µM) [18][19][20]. Elles déplacent la courbe dose-réponse du Ca 2+ vers la externe des domaines transmembranaires, faisant face au milieu extracellulaire de la cellule et dans lesquelles viendrait interagir le Calhex 231 ( Figure 4A).…”