Table 1.
Pharmacological parameters that govern the allosteric activity of CaS receptor modulators in Ca2+i mobilization, pERK1/2 and IP1 accumulation assays
| Grouped data analysis | ||||||
|---|---|---|---|---|---|---|
| Ca2+i mobilization | pERK1/2 | IP1 accumulation | ||||
| pKB ± SEM (n) | Logαβ ± SEM (αβ) | pKB ± SEM (n) | Logαβ ± SEM (αβ) | pKB ± SEM (n) | Logαβ ± SEM (αβ) | |
| Cinacalcet | 5.98 ± 0.18 (18)a | 0.66 ± 0.06 (4.6)a | 5.93 ± 0.29 (13)a | 0.46 ± 0.08 (2.9)a | 6.14 ± 0.33 (4) | 0.68 ± 0.13 (4.8) |
| NPS-R568* | 6.57 ± 0.19 (15) | 0.59 ± 0.07 (3.9) | 5.64 ± 0.18 (4) | 0.71 ± 0.06 (5.1) | 6.76 ± 0.24 (4) | 0.64 ± 0.09 (4.3) |
| Calindol* | 6.33 ± 0.23 (4) | 0.73 ± 0.10 (5.4) | 5.16 ± 0.16 (4) | 0.91 ± 0.08 (8.1) | 6.35 ± 0.23 (4) | 0.67 ± 0.09 (4.7) |
| S,R-calcimimetic B | 5.53 ± 0.16 (4) | 0.32 ± 0.03 (2.1) | 5.31 ± 0.68 (3) | 0.42 ± 0.20 (2.6) | 5.18 ± 0.31 (3) | 0.81 ± 0.14 (6.5) |
| R,R-calcimimetic B* | 7.15 ± 0.17 (4) | 0.27 ± 0.02 (1.9) | 7.08 ± 0.18 (4) | 0.47 ± 0.04 (3.0) | 7.03 ± 0.54 (4) | 0.50 ± 0.14 (3.2) |
| Nor-calcimimetic B | 6.90 ± 0.25 (7) | 0.30 ± 0.04 (2.0) | 6.80 ± 0.42 (5) | 0.32 ± 0.08 (2.1) | 7.29 ± 0.58 (4) | 0.45 ± 0.15 (3.0) |
| AC-265347* | 6.42 ± 0.22 (5) | 0.63 ± 0.08 (4.3) | 6.26 ± 0.13 (4) | 0.97 ± 0.07 (9.3) | 7.99 ± 0.26 (4) | 0.60 ± 0.09 (4.0) |
The potency of Ca2+o in the presence of increasing concentrations of modulator was fitted to an allosteric ternary complex model (Equation 2013a) to quantify the equilibrium dissociation constant (pKB) and cooperativity (αβ) of the modulators at the human CaS receptor, using a model in which the binding affinity was not constrained across pathways.
a
Datasets taken from those used in (Leach et al., 2013).
*
Significant difference in pKB and/or Logαβ between pathways (P < 0.05, F-test).