Collect. Czech. Chem. Commun. 2006, 71, 912-928

Nucleoside Prodrugs of A3 Adenosine Receptor Agonists and Antagonists

Pedro Besadaa, Liaman K. Mamedovaa, Krishnan K. Palaniappana, Zhan-Guo Gaoa, Bhalchandra V. Joshia, Lak Shin Jeongb, Mortimer M. Civanc and Kenneth A. Jacobsona,*

a Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, U.S.A.
b Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
c Departments of Physiology and Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A.


9-(β-D-Ribosfuranosyluronamide)adenine derivatives that are selective agonists and antagonists of the A3 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-N6-(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 A3AR 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 A3AR agonists and antagonists for future evaluation in vivo.

Keywords: Purines; Nucleosides; G protein-coupled receptors; Adenosine receptors; Receptor binding assays; Adenylate cyclase; Prodrugs.

References: 29 live references.