The passage of nucleosides across the plasma membrane of erythrocytes is a membrane-mediated process which is strongly inhibited by derivatives of 9-beta-D-ribofuranosylpurine (1) with S, O, or N atoms at the purine 6 position bearing variously substituted arylalkyl groups. In this structure-activity study, nucleoside derivatives were compared in respect to their ability to inhibit a transport-dependent aspect of nucleoside metabolism in erythrocytes, the synthesis of inosine from external guanosine and hypoxanthine. 6-Benzylthio, 6-benzylamino, and 6-benzyloxy derivatives of 1 were inhibitory at 10(-5)-10(-6) M and the similarity of their activities suggested that alkylation of the transporter as the mechanism of transport inhibition was unlikely. The hydrophobicity of the 6-position substituents appeared to contribute importantly to inhibitory activity. Although replacement of the ribofuranose moiety by other sugars reduced inhibitory activity, compounds with 9-butyl groups were inhibitory. 6-[(2-Hydroxy-5-nitrobenzyl)thio] derivatives of 1 were the most potent of the inhibitors tested, being active at about 10(-7) M.