5 '-O-alkyl ethers of N,2-substituted adenosine derivatives: Partial agonists for the adenosine A(1) and A(3) receptors

New N,5'-di- and N,2,5'-trisubstituted adenosine derivatives were synthesiz ed in good overall yields. Appropriate 5-O-alkyl-substituted ribose moietie s were coupled to 6-chloropurine or 2,6-dichloropurine via Vorbruggen's gly cosylation method. Subsequent amination and deprotection of the intermediat es yielded compounds 18-35. Binding affinities were determined for rat aden osine A(1) and A(2A) receptors and the human A(3) receptor. The ability of compounds 18-35 to inhibit forskolin-induced (10 muM) cyclic AMP (cAMP) pro duction and their ability to stimulate guanosine 5'-O-(3-[S-35]thio)triphos phate ([S-35]GTP gammaS) binding, via either the adenosine A(1) receptor or the adenosine A(3) receptor, were assessed. N-Cyclopentyl-substituted aden osine derivatives displayed affinities in the low nanomolar range for the a denosine A(1) receptor, whereas N-(3-iodobenzyl)-substituted derivatives ha d high affinity for the adenosine A(3) receptor. Compound 22 had the highes t affinity for the adenosine A(3) receptor (K-i value of 16 nM), and compou nds 20 and 26 had the highest affinities for the adenosine A(3) receptor (K -i values of 4 and 3 nM, respectively). A chlorine substituent at the 2-pos ition either did not affect or slightly increased the adenosine A(3) recept or affinity, whereas the A(3) receptor affinity was affected differently, d epending on the N-substituent. Furthermore, the introduction of chlorine sl ightly increased the A(3)/A(1) selectivity ratio. At the 5 ' -position, an O-methyl substituent induced the highest adenosine A(1) receptor affinity, whereas an O-ethyl substituent did so for the A(3) receptor. All compounds showed partial agonistic effects in both the cAMP and [S-35]GTP gammaS assa ys, although more marked in the latter assay. In general, the 2-chloro deri vatives seemed to have lower intrinsic activities compared to the 2-H-subst ituted compounds on both the adenosine A(1) and the adenosine A(3) receptor s. The compounds with an N-(3-iodobenzyl) substituent displayed the lowest intrinsic activities. Finally, all compounds also showed partially antagoni stic behavior in the [S-35]GTP gammaS assay.