Variable-slope Models

FIGURE 10.7 Figure illustrating the comparison of concentration-response curves to two full agonists. Equations describe response in terms of the operational model (variable slope version equation see Section 10.6.1). Schematic indicates the interacting species in this case, two full agonists A1 and A2 activating a common receptor R to produce response. Boxes show the relevant measurements (EPMRs) and definitions of the parameters of the model used in the equation. 

The operational model, as presented, shows dose-response curves with slopes of unity. This pertains specifically only to stimulus-response cascades where there is no cooperativity and the relationship between stimulus ([AR] complex) and overall response is controlled by a hyperbolic function with slope = 1. In practice, it is known that there are experimental dose-response curves with slopes that are not equal to unity and there is no a priori reason for there not to be cooperativity in the stimulus-response process. To accommodate the fitting of real data (with slopes not equal to unity) and the occurrence of stimulus-response cooperativity, a form of the operational model equation can be used with a variable slope (see Section 3.13.4) ... 

Operational model forcing function for variable slope (3.13.4)... 

This model also can accommodate dose-response curve having Hill coefficients different from unity. This can occur if the stimulus-response coupling mechanism has inherent cooperativity. A general procedure can be used to change any receptor model into a variable slope operational function. This is done by passing the receptor stimulus through a forcing function. 

Operational Model Forcing Function for Variable Slope... 

Therefore, the operational model for agonism can be rewritten for variable slope by passing the stimulus equation through the forcing function (Equation 3.51) to yield... 

Operational model for partial agonist interaction with agonist variable slope... 

One-way analysis of variance, 229-230, 230f—231f Operational model derivation of, 54-55 description of, 45—47, 46f function for variable slope, 55 for inverse agonists, 221 of agonism, 47f orthosteric antagonism, 222 partial agonists with, 124, 220-221 Opium, 147 Orphan receptors, 180 Orthosteric antagonism... 

Functional model for hemi-equilibrium effects variable slope (11.5.9). 

Orthosteric insurmountable antagonism operational model with variable slope (11.5.11). 

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