TABLE 4

Comparison of parameters describing CaSR allosteric interactions analyzed with different allosteric models

CaSR allosteric interactions with Embedded Image in Ca2+i mobilization assays were analyzed with the original operational model of agonism and allosterism (eqs. 5 or 6) vs. the operational model of allosterism with cooperative agonist binding (eqs. 7 or 8) to determine Embedded Image potency, efficacy, and affinity; modulator affinity, cooperativity, and transducer or binding slope; and maximum system response.

ParameterEmbedded Image vs. CinacalcetEmbedded Image vs. NPS2143
eq. 5eq. 7eq. 6eq. 8
pEC503.3 ± 0.013.3 ± 0.01n.d.n.d.
pKA [KA (mM)]n.d.n.d.3.6 ± 0.2 (0.3)2.9 ± 0.1 (1.3)
pKB [KB (µM)]6.3 ± 0.04 (0.5)5.8 ± 0.1 (1.6)6.6 ± 0.04 (0.3)7.3 ± 0.1 (0.05)
Log τA (τA)n.d.n.d.0.2 ± 0.1 (1.6)1.8 ± 0.1 (63)
Log τB (τB)n.a. (0)n.a. (0)n.a. (0)n.a. (0)
Log αβ (αβ)0.5 ± 0.01 (3.2)1.4 ± 0.1 (25)−0.2 ± 0.1 (0.6)−1.7 ± 0.1 (0.02)
n2.8 ± 0.1a2.8 ± 0.1a12 ± 4.0a3.5 ± 0.2a
Em (% ionomycin)79 ± 1.080 ± 1.078 ± 1.080 ± 2
  • Dfd, degrees of freedom denominator; Dfn, degrees of freedom numerator; Em, maximum system response; Log αβ (αβ), modulator cooperativity; Log τA (τA), Embedded Image efficacy; Log τB (τB), modulator efficacy; Embedded Image efficacy; n, transducer or binding slope; n.a., no agonist activity [log τB fixed to −100 (τB 0)]; n.d., not determined; pEC50, Embedded Image potency; pKA (KA), Embedded Image affinity; pKB (KB), modulator affinity .

  • a An F test determined that data were fitted best when the transducer or binding slopes were different from unity. The F data used to test the hypothesis that n differed from 1 were the following: eq. 5 cinacalcet P < 0.0001, F [(Dfn, Dfd) 1249 (1, 2429)]; eq. 5 NPS2143 P < 0.0001, F [(Dfn, Dfd) 1022 (1, 908]; eq. 7 cinacalcet P < 0.0001, F [(Dfn, Dfd) 1241 (1, 2429)]; and eq. 7 NPS2143 P < 0.0001, F [(Dfn, Dfd) 504.5 (1, 907)].