Full and partial agonistic behaviour and thermodynamic binding parameters of adenosine A 1 receptor ligands

Abstract

The inhibitory effect of forskolin-stimulated 3′,5′ -cyclic monophosphate (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 times their K i , inhibitory binding constants, determined in parallel by [ 3H] N 6-cyclohexyladenosine binding to adenosine A 1 receptors on adipocyte rat membranes which guaranteed full receptor occupancy. Some drugs were able to inhibit the forskolin-induced c-AMP accumulation by 100% (full agonists, intrinsic activity = 1) but others only to a lesser extent, ranging from 80% to 50% (partial agonists, intrinsic activities in the 0.8-0.5 interval). These efficacy data were correlated with the thermodynamic binding parameters (free energy, enthalpy and entropy) obtained in rat brain membranes by equilibrium constant measurements and van 't Hoff in the 0°–30°C range. The positive correlation between intrinsic activity and entropy changes ( r = 0.88, n = 8, P <0.01) points to the possibility of obtaining information about the full spectrum of activities of adenosine analogues from in vitro binding assays and suggests some considerations on the possible drug-receptor interaction mechanism.