Towards a Thermodynamic Definition of Efficacy in Partial Agonism: I Concentration-Response Theory for Explicit Agonist and Antagonist Complexes

The pharmacological characteristics of a partial agonist, namely its binding and efficacy, are transposed, here, to give more insight into the mode of binding of the requisite agonist and antagonist bound complexes. Simple proportionality relationships of the efficacy to the overall binding define the agonist and antagonist binding constants. The advantage of such description lies in determining the thermodynamic profiles of the respective complexes by simple temperature variation. The enthalpic difference between agonist and antagonist complexes becomes a function of the efficacy, e alone, the thermodynamic scale ratio, e / (1-e), yielding this value directly. The concentration-response theory for two bound ligand conformer complexes, one of which yields an agonist response is examined using a simple adaptation of the Black and Leff model of agonism. A selected tissue response, the chronotropic in guinea-pig right atria, dominated by a single receptor, the β1 -adrenergic under normal signal amplification conditions, was selected. The chronotropic response accurately obeys a hyperbolic dose-response form, a condition for the model’s applicability and component profiles are exemplified at 30.0°C. The precision was found sufficient to evaluate the thermodynamics of the respective complexes over a 15°C range of temperature. in a second paper.