Periodate oxidation of eight N6-substituted adenosine derivatives was performed with the aim of oxidizing the vicinal 2' and 3' hydroxyl groups of the ribose moiety. A thermodynamical and pharmacological characterization of the products of this transformation allowed us to verify that oxidized adenosine analogues act as agonists at adenosine A1 receptors. The dependence of their association constants on temperature indicates that their binding is entropy driven, a feature typical of adenosine A1 receptor agonists; moreover all synthesized compounds were able to fully inhibit the forskolin induced c-AMP accumulation in rat isolated adipocytes. This is the first report suggesting that the presence of an intact ribose moiety is not necessary for agonistic activity at adenosine A1 receptor. In fact periodate oxidation of the ribose moiety yields a dialdehyde and it is recognized that nucleoside dialdehydes are complex equilibrium mixtures of cyclic and acyclic hydrates and hemiacetals.