Influence of the molecular structure of N 6-(ω-aminoalkyl)adenosines on adenosine receptor affinity and intrinsic activity

Abstract

The affinities of a series of N 6-(ω-aminoalkyl)adenosines as probes for A 1 and A 2 adenosine receptors were determined in various radioligand binding assays and the intrinsic activities were measured in adenylate cyclase assays. Clear species differences were noticed for A 1 receptor affinity of these adenosine receptor agonists, the compounds being more active in calf than in rat brain tissue. The affinity profile within the series was, however, rather similar in both membrane preparations, with N 6-9-aminononyladenosine displaying highest affinity. The A 2 receptor affinities were comparable to values measured for the A 1 receptor in its low affinity state, as assessed with a radiolabelled antagonist in the presence of 1 mM GTP. Calculation of the intrinsic activities of the adenosine analogues from their modulating action on adenylate cyclase showed almost all the compounds to be equally effective to (−)-N 6-(R-phenylisopropyl) adenosine, on either A 1 or A 2 adenosine receptors. N 6-3-Aminopropyl- and N 6-12-aminododecyladenosine, however, proved to be partial agonists, the first on A 1 and the second on A 2 adenosine receptors. The data are used as the basis for a discussion of adenosine receptor subtype selectivity and intrinsic activity in general.