Operational model parameters for the allosteric interaction between LY2033298 and various ligands at either the wild type (WT) or DREADD M4 mAChR
Except as indicated otherwise, parameter values represent the mean ± S.E.M. from three to six experiments performed in triplicate. The letters in parentheses denote corresponding ligands in the operational model (eq. 7; A = agonist; B = modulator).
Parameter | LY2033298 (A) vs Clozapine (B) M4 WT | LY2033298 (A) vs CNO (B) M4 WT | ACh (A) vs LY2033298 (B) M4 DREADD |
|---|---|---|---|
| pKA | 5.43a | 5.43a | 3.53 ± 0.19 |
| pKB | 7.87 ± 0.17 | 6.07 ± 0.09 | 5.39 ± 0.73 |
| Log α | 0.65a | 0.55a | 0a |
| Log β | −2.61 ± 0.83 | N.F. | 2.19 ± 0.81 |
| (β = 0.002) | (β → 0) | (β = 155) | |
| Log τA | 1.66 ± 0.13 | 1.56 ± 0.07 | 0.38 ± 0.12 |
| Em | 47.1 ± 4.7 | 69.0 ± 3.8 | 53.7 ± 2.9 |
|
n
| 1.52 ± 0.46 | 1.36 ± 0.49 | 1.63 ± 0.36 |
pKA, negative logarithm of the dissociation constant of ligand A (agonist); pKB, negative logarithm of the dissociation constant of ligand B (modulator); Log α, logarithm of the binding cooperativity factor; Log β, logarithm of the activation cooperativity factor; Log τA, logarithm of the agonist operational efficacy parameter; Em, maximum system response level; n, transducer slope factor; N.F., not fitted; parameter estimate was ambiguous and approached a lower boundary (less than −90), indicating that the value of β was practically indistinguishable from zero.
↵ a Fixed as a constant based on the value determined in the radioligand binding assay.