TABLE 1

Representative CaSR agonists or endogenous and small-molecule allosteric modulators and their pharmacological properties

LigandStructure(Cell Type or Model, Assay)Potencya or AffinitybCooperativityc with Ca2+oReferences
Agonists
 Ca2+oCa2+Human, PTH releasepEC50 2.9NABrown, 1983, 1991; Ramirez et al., 1993; Quinn et al., 1997; Gregory et al., 2018, 2020
Parathyroid cell, PTH releasepEC50 3.0NA
HEK293, Ca2+ipEC50 2.5–3.5NA
HEK293, Ca2+ipKB 3.0NA
 SpermineEmbedded ImageHEK293, Ca2+ipEC50 3.3–4.4NAQuinn et al., 1997; Gregory et al., 2018
 NeomycinEmbedded ImageHEK293, Ca2+ipEC50 4.4NAMcLarnon et al., 2002
PAMs
 L-TrpEmbedded ImageHEK293, Ca2+ipEC50 2.6NDConigrave et al., 2000
 CinacalcetEmbedded ImageHEK293, Ca2+ipKB 5.9–6.72.6–4.7Davey et al., 2012; Leach et al., 2013, 2016; Cook et al., 2015; Diepenhorst et al., 2018
HEK293, IP1pKB 6.12.6–4.8
HEK293, pERK1/2pKB 5.9–6.51.3–2.9
HEK293, membrane rufflingpKB 8.12.6
HEK293, SRF-RE lucdpKB 7.14.5
 NPS R-568Embedded ImageHEK293, Ca2+ipKB 6.0–6.63.0–3.9Lu et al., 2009; Davey et al., 2012; Cook et al., 2015; Gregory et al., 2018; Keller et al., 2018
CHO, aequorinpKB 6.22.7
CHO/HEK293, IP1pKB 6.2–6.84.3–4.5
HEK293, pERK1/2pKB 5.6–6.62.0–5.1
HEK293, membrane rufflingpKB 9.41.7
 CalindolEmbedded ImageHEK293, Ca2+ipKB 6.35.4Cook et al., 2015
HEK293, IP1pKB 6.44.7
HEK293, pERK1/2pKB 5.28.1
 EvocalcetEmbedded ImageHEK293, Ca2+ipEC50 7.0NDKawata et al., 2018
R,R-calcimimetic BEmbedded ImageHEK293, Ca2+ipKB 7.21.9Cook et al., 2015
HEK293, IP1pKB 7.03.2
HEK293, pERK1/2pKB 7.13.0
 AC265347Embedded ImageHEK293, Ca2+ipKB 6.2–6.42.5–4.3Cook et al., 2015; Leach et al., 2016; Diepenhorst et al., 2018
HEK293, IP1pKB 7.3–8.04.0–4.7
HEK293, pERK1/2pKB 6.1–6.74.5–10
HEK293, SRF-RE lucpKB 6.213
 BTU compound 13Embedded ImageHEK293, Ca2+ipKB 6.73.2Diepenhorst et al., 2018
HEK293, IP1pKB 7.22.9
HEK293, pERK1/2pKB 6.21.2
HEK293, SRF-RE lucpKB 6.517
 EtelcalcetideEmbedded ImageHEK293, IP1pEC50 4.6NDWalter et al., 2013
NAMs
 NPS 2143Embedded ImageHEK293, Ca2+ipKB 6.2–6.70.3–0.5Davey et al., 2012; Leach et al., 2016
HEK293, pERK1/2pKB 6.2–6.60.3–0.6
HEK293, membrane rufflingpKB 7.80.3
 NPSP795Embedded ImageHEK293, assay not disclosedpIC50 7.1NDKumar et al., 2010
 RonacaleretEmbedded ImageHEK293, Ca2+ipKB 6.40.03Josephs et al., 2019
 JTT-305/MK-5442Embedded ImagePC12h, zif lucepIC50 7.9NDShinagawa et al., 2011
 ATF936Embedded ImageHEK293, Ca2+ipKB 7.60.005Josephs et al., 2019
 BMS compound 1Embedded ImageHEK293, Ca2+ipKB 7.00.03Josephs et al., 2019
 3H-pyrimidine-4-one compound (R)-2hEmbedded ImageHEK293, Ca2+ipKB 7.80.009Josephs et al., 2019
 Benzimidazole compound 40Embedded ImageHamster fibroblasts, Ca2+ipIC50 8.4NDGerspacher et al., 2010
Mixed PAM/NAM
 Calhex 231Embedded ImageHEK293, Ca2+ipKB 6.5NDGregory et al., 2018
  • luc, luciferase; NA, not applicable; ND, not determined; SRF-RE, serum response factor–response element; zif, zinc finger.

  • a pEC50 or pIC50 is the negative logarithm of ligand concentration that mediates a 50% response determined in a functional assay. For a PAM or NAM, the pEC50 or pIC50 is the modulator’s ability to half maximally potentiate or inhibit a single Ca2+o concentration (usually EC80 or EC20, respectively).

  • b pKB is the negative logarithm of the ligand concentration that achieves 50% receptor occupancy (the equilibrium dissociation constant) determined in a functional assay in which the interaction between an agonist (usually Ca2+o) and the PAM or NAM was fitted to an operational model of allosterism or an allosteric ternary complex model.

  • c αβ values between the allosteric modulator and Ca2+o, in which α is the binding cooperativity, and β is a scaling factor that describes the effect of the modulator on agonist efficacy. Because of a lack of commercially available CaSR radioligands, cooperativity was estimated as a composite αβ value in functional assays.

  • d Serum response factor–response element luciferase reporter gene assay.

  • e Zif promoter luciferase reporter gene assay.