Binding thermodynamics and intrinsic activity of adenosine A(1) receptor ligands

A thermodynamic analysis of the binding to rat cortex adenosine A(1) recept ors of 5'-deoxyribose-N-6-cyclopentyladenosine (full agonist) and several 8 -alkylamino homologues of N-6-cyclopentyladenosine (partial agonists) was p erformed, The intrinsic activity of the compounds was also evaluated by mea suring the inhibition of forskolin-stimulated 3'-5'-cyclic adenosine monoph osphate (c-AMP) levels in isolated epididymal rat adipocytes, Standard free energy (Delta G degrees), enthalpy (Delta H degrees) and entropy (Delta S degrees) of the binding equilibrium were determined by affinity measurement s carried out at different temperatures (0, 10, 20, 25, 30 degrees C). Affi nity constants of drug-receptor interactions were obtained by displacement experiments in the presence of 1nM [H-3] N-6-cyclohexyladenosine. Levels of c-AMP were evaluated by performing competitive binding assays. As the affi nity of the ligands was found to increase with temperature enhancement, the binding of full and partial agonists is therefore totally entropy-driven. Standard entropy values of a wide series of adenosine derivatives, includin g the compounds under examination, are strictly correlated to those of intr insic activity. Similarly, Delta S degrees values appear correlated to the in vivo ability of the adenosine derivatives to inhibit rat heart rate. The rmodynamic data of adenosine A(1) receptor ligands are proposed as an indic ator of their pharmacodynamics. (C) 2000 Elsevier Science Inc. All rights r eserved.