NUCLEOSIDE PRODRUGS OF A ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS.

9-(β-D-Ribosfuranosyluronamide)adenine derivatives that are selective agonists and antagonists of the A adenosine receptor (AR) have been derivatized as prodrugs for delivery. The free hydroxy groups at the 2' and 3' positions of the agonists 2-chloro- -(3-iodobenzyl)-9-(-methyl-(β-D-ribosfuranosyluronamide)adenine , the corresponding 4'-thio nucleoside , and antagonists and (5'-,-dimethylamides related to and , respectively) were derivatized through simple acylation reactions. The prodrug derivatives were tested in radioligand binding assays at ARs and in a functional assay of adenylate cyclase at the AAR and found to be considerably less active than the parent drugs. The hydrolysis of nucleoside 2',3'-diesters to regenerate the parent compound in the presence of human blood was demonstrated. 2',3'-Dipropionate esters of and were readily cleaved in a two-step reaction to regenerate the parent drug, on a time scale of two hours. The cleavage of a 2',3'-dihexanoate ester occurred at a slower rate. This indicates that the prodrugs are suitable as masked forms of the biologically active AAR agonists and antagonists for future evaluation .