Synthesis and study of 5 '-ester prodrugs of N-6-cyclopentgladenosine, a selective A(1) receptor agonist

Purpose. A series of 5 ' -esters of N " -cyclopentyladenosine (CPA) were pr epared with the aim to improve stability and bioavailability of selective A (1) agonists. Log P values, stability, affinity, and activity toward human adenosine A, receptors were evaluated. Methods. An appropriate synthetic procedure was adopted to avoid concomitan t deamination at position 6. Log P values were obtained by the Mixxor syste m. The stability of CPA and its 5 ' -ester was evaluated in human plasma an d whole blood and analyzed with highperformance liquid chromatography. The affinities to human A, receptor expressed by N-6-cyclohexyladenosine cells were obtained by binding experiments. The activities were evaluated by meas urements of the inhibition of forskolin stimulated 3 ' -5 ' -cyclic adenosi ne monophosphate, performing competitive binding assays. Results. All prodrugs were more lipophilic than CPA, and their hydrolysis, in whole blood and in plasma, was found related, respectively, to the lengt h and hindrance of 5 ' -substituents. Affinity and activity values indicate d a very weak interaction toward adenosine A, receptor of the intact prodru gs. Conclusions. We propose 5 ' -esters of CPA, characterized by suitable lipop hilicity and elevated degree of stability in physiological fluids, as possi ble canditates for CPA prodrugs.