Binding thermodynamics at A(1) and A(2A) adenosine receptors

Only recently the binding equilibrium of a number of ligands at adenosine A(1) and A(2a) receptors has been analyzed from a thermodynamic point of view. This approach presents the advantage, with respect to usual affinity constant measurements, of a greater capability to give information about the molecular mechanisms underlying the binding process. All available data agree in indicating that, for both A(1) and A(2a) receptors, agonist binding of adenosine derivatives was totally entropy-driven, while xanthine antagonist binding was essentially enthalpy-driven. The differences in thermodynamic behaviour of A(1) and A(2a) agonists and antagonists could be interpreted in terms of a simplified general model of drug-receptor interaction, which accounted for the role played by the ribose moiety and N-6-substituents of adenosinic drugs in determining both affinity and intrinsic activity properties. In the frame of this model, measurements of thermodynamic parameters of N-6-monosubstituted agonists allowed to hypothesize, for the first time, the existence of partial agonists to adenosine A(1) receptors, as now confirmed experimentally. All thermodynamic data concerning the interaction of all ligands studied with A(1) and A(2a) receptors are briefly discussed in terms of the enthalpy-entropy compensation phenomenon which appears to be widely determined by the reorganization of solvent molecules in the binding process.