FULL AND PARTIAL AGONISTIC BEHAVIOR AND THERMODYNAMIC BINDING PARAMETERS OF ADENOSINE-A1-RECEPTOR LIGANDS

The inhibitory effect of forskolin-stimulated 3',5'-cyclic monophospha te (c-AMP) synthesis in isolated rat adipocytes has been measured for eight typical adenosine receptor agonists. The percent inhibition was evaluated using concentrations of each compound corresponding to 100 t imes their K(i), inhibitory binding constants, determined in parallel by [H-3]N6-cyclohexyladenosine binding to adenosine A, receptors on ad ipocyte rat membranes which guaranteed full receptor occupancy. Some d rugs were able to inhibit the forskolin-induced c-AMP accumulation by 100% (full agonists, intrinsic activity = 1) but others only to a less er extent, ranging from 80% to 50% (partial agonists, intrinsic activi ties in the 0.8-0.5 interval). These efficacy data were correlated wit h the thermodynamic binding parameters (free energy, enthalpy and entr opy) obtained in rat brain membranes by equilibrium constant measureme nts and van 't Hoff plots in the 0-degrees-30-degrees-C range. The pos itive correlation between intrinsic activity and entropy changes (r = 0.88, n = 8, P < 0.01) points to the possibility of obtaining informat ion about the full spectrum of activities of adenosine analogues from in vitro binding assays and suggests some considerations on the possib le drug-receptor interaction mechanism.