title: Full and partial agonistic behaviour and thermodynamic binding parameters of adenosine A1 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 Ki, inhibitory binding constants, determined in parallel by [3H]N6-cyclohexyladenosine binding to adenosine A1 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 plots in the 0 degrees-30 degrees 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.
authors.affiliation: Institute of Pharmacology, University of Ferrara, Italy.
authors.forename: P A
authors.initials: PA
authors.lastname: Borea
authors.forename: K
authors.initials: K
authors.lastname: Varani
authors.forename: A
authors.initials: A
authors.lastname: Dalpiaz
authors.forename: A
authors.initials: A
authors.lastname: Capuzzo
authors.forename: E
authors.initials: E
authors.lastname: Fabbri
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis; D066298:In Vitro Techniques; D008297:Male; D008962:Models, Theoretical; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013816:Thermodynamics
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D018047:Receptors, Purinergic P1; C027513:N(6)-cyclohexyladenosine; D000242:Cyclic AMP; D000241:Adenosine