NUCLEOSIDE PRODRUGS OF A_3 ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS

摘要

9-(beta-D-Ribosfuranosyluronamide)adenine derivatives that are selective agonists and antagonists of the A_3 adenosine receptor (AR) have been derivatized as prodrugs for in vivo delivery.The free hydroxy groups at the 2' and 3' positions of the agonists 2-chloro-N~6-(3-iodo-benzyl)-9-(N-methyl-(beta-D-ribosfuranosyluronamide)adenine 2b,the corresponding 4'-thio nucleoside 2c,and antagonists 4a and 4b (5'-N,N-dimethylamides related to 2b and 2c,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 A_3AR 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 2b and 4a 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 A_3AR agonists and antagonists for future evaluation in vivo.