Calcium Sensing Receptor Activators: Calcimimetics

Abstract

The calcium sensing receptor (CaR) is a G protein-coupled receptor (GPCR) that plays a fundamental role in serum calcium homeostasis. The CaR is expressed on the chief cells of the parathyroid gland and is responsible for controlling the secretion of parathyroid hormone (PTH). PTH acts on several organs including the bone, kidney, and intestine to tightly regulate the concentration of serum calcium. Substances other than calcium that activate the CaR are referred to as calcimimetics. Calcimimetics that bind to the CaR as agonists are referred to as type I. Type II calcimimetics bind to a site that is distinct from the physiological ligand and function as positive allosteric modulators of the CaR. Type II calcimimetics amplify the sensitivity of the CaR to serum calcium and are thus able to lower the concentration of serum PTH. Calcimimetics are being pursued as therapeutics for the treatment of disorders that are characterized by elevated levels of PTH such as primary and secondary hyperparathyroidism (primary HPT and secondary HPT). In this review, we provide an overview of key results in the discovery of cinacalcet HCl (Sensipar in the US, Mimpara in Europe). In addition, other recently disclosed type II calcimimetics are discussed.

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

“…The functional expression of CaSR was assessed in cTAL and CCD by studying the effect of two distinct CaSR activators on cytosolic Ca concentration ([Ca 2+ ]i): (a) a polyvalent cation (neomycin) that binds to the extracellular N-terminal CaSR domain, mimics Ca 2+ , then activates CaSR (51); and (b) NPS-R568, a hydrophobic low-molecular-weight drug that allosterically activates CaSR (52,53). The technique used for [Ca 2+ ]i measurement in single microdissected tubules has been described (54).…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…The medicinal chemistry of calcimimetics has been reviewed by Harrington and Fotsch (2007). The first positive allosteric modulators of the CaSR were the phenylalkylamines NPS568 and its deschloro-derivative NPS467 (Table 12, compound I) which were obtained in a derivatization program using fendiline as a starting point (Nemeth et al, 1996.…”

Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

“…As mentioned earlier, allosteric modulators of the CaR bind to the seven TM region of the CaR, not the ECD, which is the binding site for orthosteric ligands. CaR allosteric modulators that have been studied in some detail include the calcimimetics cinacalcet (Evenepoel, 2008), NPS R-568 (Harrington and Fotsch, 2007), and calindol ) and the calcilytics NPS 2143 (Gowen et al, 2000) and Calhex 231 (Petrel et al, 2003) (Fig. 3B).…”