Fig. 4.

Simulation and analysis of the response of orthosteric ligands at a constitutively active receptor. a, the theoretical curves were generated using the operational model for the total stimulus (eq. 27) with the latter defined as the summation of the active states of the quaternary (DR_s*GX) and ternary (R_s*GX) complexes. These were simulated using the quaternary complex model described in Ehlert et al. (2011). The log affinity constant of the agonists A to D for the inactive state was 5.0, and that for the inverse agonists (E–G) was 7.0. The K_b value expressed relative to K_a is given in the symbol key. The parameters of the model were the same as those given in the legend to Fig. 3. b, nonlinear regression analysis of the concentration-response curve of agonist A according to eq. 52. During regression analysis, K_E was constrained to a range of values shown on the abscissa. The corresponding estimates of log ε and the residual sum of squares are plotted against the constrained value of log K_E.