Biological activities of n6,C8-disubstituted adenosine derivatives as partial agonists at rat brain adenosine A1 receptors

C8-substituted derivatives of the adenosine A1 receptor-selective agonist N6-cyclopentyladenosine (CPA) were evaluated as potential partial adenosine A1 receptor agonists in rat brain. Potencies and efficacies of 8-alkylamino-CPA derivatives were determined in G protein activation assays by their ability to stimulate binding of [35S]guanosine-5'-(gamma-thio)triphosphate ([35S]GTPgammaS) to rat forebrain membranes, by their ability to inhibit forskolin-stimulated adenylate cyclase, and by inhibition of evoked field excitatory postsynaptic potentials (field EPSPs) in hippocampal slices. EC50 values around 1 microM were determined for all C8-substituted CPA derivatives. Increase in chain length of the substituent gradually reduced agonist efficacy in [35S]GTPgammaS binding studies. Only C8-methylamino-, C8-ethylamino- and C8-propylamino-CPA inhibited forskolin-stimulated adenylate cyclase. In contrast, 8-methylamino- and 8-butylamino-CPA were the compounds of highest intrinsic activity in inhibition of field EPSPs in the hippocampus, followed by 8-ethylamino-CPA. 8-Cyclopentylamino-CPA was without effect in this tissue, and the propylamino derivative, when applied cumulatively, caused an inhibition which was smaller the higher the concentration used and the longer the application, which is suggestive of drug-induced desensitization. These data indicate that 8-aminoalkyl-substituted CPA derivatives act as partial agonists on the brain and may serve as valuable tools to dissect adenosine A1 receptor mediated signal trafficking in various organs.