Ligand | Structure | (Cell Type or Model, Assay) | Potencya or Affinityb | Cooperativityc with Ca2+o | References |
---|---|---|---|---|---|
Agonists | |||||
Ca2+o | Ca2+ | Human, PTH release | pEC50 2.9 | NA | Brown, 1983, 1991; Ramirez et al., 1993; Quinn et al., 1997; Gregory et al., 2018, 2020 |
Parathyroid cell, PTH release | pEC50 3.0 | NA | |||
HEK293, Ca2+i | pEC50 2.5–3.5 | NA | |||
HEK293, Ca2+i | pKB 3.0 | NA | |||
Spermine | HEK293, Ca2+i | pEC50 3.3–4.4 | NA | Quinn et al., 1997; Gregory et al., 2018 | |
Neomycin | HEK293, Ca2+i | pEC50 4.4 | NA | McLarnon et al., 2002 | |
PAMs | |||||
L-Trp | HEK293, Ca2+i | pEC50 2.6 | ND | Conigrave et al., 2000 | |
Cinacalcet | HEK293, Ca2+i | pKB 5.9–6.7 | 2.6–4.7 | Davey et al., 2012; Leach et al., 2013, 2016; Cook et al., 2015; Diepenhorst et al., 2018 | |
HEK293, IP1 | pKB 6.1 | 2.6–4.8 | |||
HEK293, pERK1/2 | pKB 5.9–6.5 | 1.3–2.9 | |||
HEK293, membrane ruffling | pKB 8.1 | 2.6 | |||
HEK293, SRF-RE lucd | pKB 7.1 | 4.5 | |||
NPS R-568 | HEK293, Ca2+i | pKB 6.0–6.6 | 3.0–3.9 | Lu et al., 2009; Davey et al., 2012; Cook et al., 2015; Gregory et al., 2018; Keller et al., 2018 | |
CHO, aequorin | pKB 6.2 | 2.7 | |||
CHO/HEK293, IP1 | pKB 6.2–6.8 | 4.3–4.5 | |||
HEK293, pERK1/2 | pKB 5.6–6.6 | 2.0–5.1 | |||
HEK293, membrane ruffling | pKB 9.4 | 1.7 | |||
Calindol | HEK293, Ca2+i | pKB 6.3 | 5.4 | Cook et al., 2015 | |
HEK293, IP1 | pKB 6.4 | 4.7 | |||
HEK293, pERK1/2 | pKB 5.2 | 8.1 | |||
Evocalcet | HEK293, Ca2+i | pEC50 7.0 | ND | Kawata et al., 2018 | |
R,R-calcimimetic B | HEK293, Ca2+i | pKB 7.2 | 1.9 | Cook et al., 2015 | |
HEK293, IP1 | pKB 7.0 | 3.2 | |||
HEK293, pERK1/2 | pKB 7.1 | 3.0 | |||
AC265347 | HEK293, Ca2+i | pKB 6.2–6.4 | 2.5–4.3 | Cook et al., 2015; Leach et al., 2016; Diepenhorst et al., 2018 | |
HEK293, IP1 | pKB 7.3–8.0 | 4.0–4.7 | |||
HEK293, pERK1/2 | pKB 6.1–6.7 | 4.5–10 | |||
HEK293, SRF-RE luc | pKB 6.2 | 13 | |||
BTU compound 13 | HEK293, Ca2+i | pKB 6.7 | 3.2 | Diepenhorst et al., 2018 | |
HEK293, IP1 | pKB 7.2 | 2.9 | |||
HEK293, pERK1/2 | pKB 6.2 | 1.2 | |||
HEK293, SRF-RE luc | pKB 6.5 | 17 | |||
Etelcalcetide | HEK293, IP1 | pEC50 4.6 | ND | Walter et al., 2013 | |
NAMs | |||||
NPS 2143 | HEK293, Ca2+i | pKB 6.2–6.7 | 0.3–0.5 | Davey et al., 2012; Leach et al., 2016 | |
HEK293, pERK1/2 | pKB 6.2–6.6 | 0.3–0.6 | |||
HEK293, membrane ruffling | pKB 7.8 | 0.3 | |||
NPSP795 | HEK293, assay not disclosed | pIC50 7.1 | ND | Kumar et al., 2010 | |
Ronacaleret | HEK293, Ca2+i | pKB 6.4 | 0.03 | Josephs et al., 2019 | |
JTT-305/MK-5442 | PC12h, zif luce | pIC50 7.9 | ND | Shinagawa et al., 2011 | |
ATF936 | HEK293, Ca2+i | pKB 7.6 | 0.005 | Josephs et al., 2019 | |
BMS compound 1 | HEK293, Ca2+i | pKB 7.0 | 0.03 | Josephs et al., 2019 | |
3H-pyrimidine-4-one compound (R)-2h | HEK293, Ca2+i | pKB 7.8 | 0.009 | Josephs et al., 2019 | |
Benzimidazole compound 40 | Hamster fibroblasts, Ca2+i | pIC50 8.4 | ND | Gerspacher et al., 2010 | |
Mixed PAM/NAM | |||||
Calhex 231 | HEK293, Ca2+i | pKB 6.5 | ND | Gregory 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.