Analysis of agonist-agonist interactions: the crucial influence of curve shape.

The two-receptor:one-transducer model (Leff, 1987) is here extended to analyze interactions between agonists displaying E[A] curves of different shapes, by incorporating slope factors into the separate and common parts of the transduction pathway. Interactions were modelled as the effect of one agonist, at fixed concentration, on the curve to the other. A variety of patterns of position and slope changes are predicted. These do not depend on the shape of the control curve, rather, they depend on the slope factors in the separate and common pathways. The following specific predictions are made: (1) when the common pathway is steep, curves undergo potentiation and flattening; (2) when the common pathway is flat, curves undergo right-shift and steepening; (3) when the common pathway is hyperbolic, curves undergo right-shift, with no slope change; (4) when the slope depends on the separate pathways, curves only undergo right-shift with no change in slope. The model provides a sound basis for classifying agonist interactions and for detecting additional, synergistic or antagonistic properties. This analysis indicates that methods based on dose-additivity or independence are less reliable for these purposes. The model provides a practical test, based on slope changes, to detect and quantify additional properties.