Open AccessNucleoside Prodrugs of A3 Adenosine Receptor Agonists and Antagonists
Author(s) -
Pedro Besada,
L.K. Mamedova,
Krishnan K. Palaniappan,
ZhanGuo Gao,
Bhalchandra V. Joshi,
Lak Shin Jeong,
Mortimer M. Civan,
Kenneth A. Jacobson
Publication year - 2006
Publication title -
collection of czechoslovak chemical communications
Language(s) - English
Resource type - Journals
eISSN - 1212-6950
pISSN - 0010-0765
DOI - 10.1135/cccc20060912
Subject(s) - prodrug , chemistry , in vivo , nucleoside , thio , acylation , stereochemistry , adenosine , adenosine receptor , chemical synthesis , radioligand , pharmacology , receptor , in vitro , biochemistry , agonist , microbiology and biotechnology , biology , catalysis , medicine
9-(β-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-iodobenzyl)-9-( N -methyl-(β-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 3 AR 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 3 AR agonists and antagonists for future evaluation in vivo .