[Quantitative parameters of drug-receptor interactions and receptor reserves. I. Models I-3-R and I-3-S]

On a simple model of a reaction-chain from the pharmacon-receptor complex (RA) formation the formation of a ternal complex with substrate (S) and its activation to a product the authors investigate the meaning of the term "affinity" and "internal activity" and the behaviour of the model with substrate and velocity limits at various sites. If K1 = dissociation constant of the complex RA, K2 = dissociation constant of the complex RAS, then at S1 much greater than R1 (i.e. without receptor reserve) the obtained value ED50 described usually as KA = K1K2: (K2 + [St]) and if K1 is constant it is variable in relation to the substrate concentration. In this way continuous differences of apparent affinity of the same substance to the same receptor under different biological conditions are possible. At R1 much greater than St (i.e. with receptor reserve) apparent KA = K1K2: (K2 + [Rt]) and thus K1 can be assessed by blocking receptors with an irreversible antagonist. The authors describe the calculation and very simple graphical method for assessment of basic parameters using an irreversible antagonist. After linear plotting of ED50 (= KA) on the chi-axis and maximal effects on the gamma-axis and after extrapolation of the connecting line of the two points (results without antagonist and results with antagonist) the intersecting point with the chi-axis gives value K1. This makes it possible, among others, to assess also the "intrinsic efficacy" of the substance, the ratio of receptors eliminated by the antagonist, prediction of the behaviour of typical curves during gradual elimination of receptors by a blocker and to assess possibly also the half-life of binding of the irreversible blocker with the receptor.