BINDING THERMODYNAMICS AT A(1) AND A(2A) ADENOSINE RECEPTORS

Only recently the binding equilibrium of a number of ligands at adenos ine A(1) and A(2a) receptors has been analyzed from a thermodynamic po int of view. This approach presents the advantage, with respect to usu al affinity constant measurements, of a greater capability to give inf ormation 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 entro py-driven, while xanthine antagonist binding was essentially enthalpy- driven. The differences in thermodynamic behaviour of A(1) and A(2a) a gonists and antagonists could be interpreted in terms of a simplified general model of drug-receptor interaction, which accounted for the ro le played by the ribose moiety and N-6-substituents of adenosinic drug s in determining both affinity and intrinsic activity properties. In t he 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 inter action of all ligands studied with A(1) and A(2a) receptors are briefl y discussed in terms of the enthalpy-entropy compensation phenomenon w hich appears to be widely determined by the reorganization of solvent molecules in the binding process.