Table 1. In Vitro Pharmacological Properties of mGlu5 PAMs. Data are Mean ± s.e.m. from Three to Six Independent Experiments.
| compound ID | rat pEC50a (EC50, nM) | %Glu maxb | pKBc (KB, μM) | log αβd (αβ) | log τAe (τA) | nf | basalg | Emh |
|---|---|---|---|---|---|---|---|---|
| VU0419832 | 6.94 ± 0.07 (114) | 76.2 ± 1.7 | 5.93 ± 0.02 (1.2) | 0.99 ± 0.07 (9.7) | 0.31 ± 0.03 (2.0) | 1.7 ± 0.3 | 1.1 ± 0.2 | 96.0 ± 1.1 |
| VU0455651 | 7.78 ± 0.03 (16.8) | 75.9 ± 0.3 | 6.96 ± 0.13 (0.11) | 0.97 ± 0.12 (9.2) | 0.27 ± 0.01 (1.9) | 1.9 ± 0.3 | 1.4 ± 0.4 | 97.1 ± 1.1 |
| VU0464075 | 6.94 ± 0.02 (115) | 61.8 ± 1.8 | 6.40 ± 0.04 (0.40) | 0.58 ± 0.04 (3.8) | 0.32 ± 0.02 (2.1) | 2.1 ± 0.2 | 1.8 ± 0.2 | 97.3 ± 0.5 |
| VU0447256 | 6.91 ± 0.03 (123) | 71.9 ± 2.0 | 6.09 ± 0.03 (0.81) | 0.70 ± 0.03 (5.1) | 0.24 ± 0.11 (1.8) | 2.4 ± 0.3 | 1.9 ± 0.3 | 96.6 ± 2.3 |
| VU0415133 | 6.74 ± 0.01 (181) | 73.3 ± 1.0 | 6.14 ± 0.20 (0.72) | 0.76 ± 0.04 (5.7) | 0.29 ± 0.04 (1.9) | 2.1 ± 0.2 | 2.5 ± 0.5 | 98.7 ± 1.5 |
| VU0409551 | 6.65 ± 0.01 (224) | 74.1 ± 1.0 | 5.13 ± 0.12 (7.4) | 0.97 ± 0.10 (9.4) | 0.33 ± 0.02 (2.2) | 2.2 ± 0.2 | 1.7 ± 0.4 | 97.6 ± 1.9 |
| VU0462807 | 6.63 ± 0.04 (236) | 64.9 ± 0.4 | 5.99 ± 0.05 (1.0) | 0.64 ± 0.07 (4.3) | 0.30 ± 0.02 (2.0) | 2.0 ± 0.2 | 1.6 ± 0.3 | 97.2 ± 1.4 |
| VU0464042 | 6.58 ± 0.07 (264) | 71.5 ± 0.7 | 5.90 ± 0.05 (1.3) | 0.76 ± 0.05 (5.7) | 0.29 ± 0.01 (2.0) | 2.1 ± 0.2 | 2.0 ± 0.3 | 97.9 ± 1.5 |
| VU0405372 | 6.34 ± 0.04 (456) | 48.3 ± 2.9 | 5.70 ± 0.10 (2.0) | 0.32 ± 0.04 (2.1) | 0.40 ± 0.02 (2.5) | 2.1 ± 0.2 | 1.5 ± 0.2 | 95.9 ± 0.7 |
| VU0408899 | 5.37 ± 0.07 (4200) | 79.4 ± 3.0 | 4.94 ± 0.04 (12) | 0.78 ± 0.05 (6.1) | 0.36 ± 0.01 (2.3) | 2.3 ± 0.2 | 1.5 ± 0.3 | 97.2 ± 0.7 |
Negative logarithm of the modulator concentration required to induce half-maximal potentiation of an EC20 glutamate response derived from curve fits in Figure 1.
Maximal level of potentiation of EC20 glutamate in the presence of indicated PAM, expressed as a percentage of the response to 1 mM glutamate.
Negative logarithm of the equilibrium dissociation constant of indicated allosteric modulator, estimated by application of the OMA to functional interaction studies with glutamate (Supplemental Figure 1).
Composite cooperativity factor describing the magnitude and direction of the allosteric interaction between indicated modulator and glutamate for iCa2+ mobilization.
Coupling efficiency of glutamate for iCa2+ mobilization in HEK293A-mGlu5 (rat) cells.
Nonlinear transducer function that links agonist occupancy to response.
Basal response of HEK293A-mGlu5 (rat) cells for iCa2+ mobilization in response to vehicle.
Maximum possible system response, expressed as a percentage of the response to 1 mM glutamate.