Stimulus amplification, efficacy, and the operational model. Part I--binary complex occupancy mechanisms.
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A simple function, developed to represent the stimulus produced at the n -th step of a multistep signaling sequence, is applied to the classic model of agonist-receptor interaction. The model indicates that the relative efficacy of two agonists can be easily estimated from three experimental measures: maximal response, EC50, and apparent dissociation constant. Efficacy ratios obtained in this manner appear statistically and mathematically equivalent to those estimated with null-based methods. Enhancement of both maximal response (vertical amplification) and potency (horizontal amplification) are demonstrated to result from the interaction between highly efficacious agonists and signal transduction mechanisms. Both properties, not just relative maxima, must therefore be examined when comparing relative efficacy. Three additional generalized stimulus-response models are developed and shown to be functionally equivalent. Increasing the complexity of the function used to represent stimulus amplification does not appear to alter the conclusions derived based on the simple model of stimulus amplification. Analysis of the results also reveals a close relationship between mechanistic and operational modes of drug action, and allows operational parameters to be given mechanistic interpretation.
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