NUCLEOSIDE PRODRUGS OF A3 ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS

Pedro Besada, Liaman K Mamedova, Krishnan K Palaniappan, Zhan-Guo Gao, Bhalchandra V Joshi, Lak Shin Jeong, Mortimer M Civan, Kenneth A Jacobson, Pedro Besada, Liaman K Mamedova, Krishnan K Palaniappan, Zhan-Guo Gao, Bhalchandra V Joshi, Lak Shin Jeong, Mortimer M Civan, Kenneth A Jacobson

Abstract

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

Figures

Fig. 1
Fig. 1
Time course of degradation of prodrug diesters (▲), compounds 5 (a), 6 (b), and 13 (c) and the appearance of the parent 2′,3′-dihydroxy nucleosides (●), i.e. 2b for (a) and (b) and 4a for (c), in whole human blood at 37 °C. In each case, the appearance of the isomeric mixture of 2′ and 3′ monoesters (◼), an intermediate stage in the regeneration of the parent compounds, was also followed. Analysis was performed following cell lysis and ethyl acetate extraction, as described in Experimental. The y-axis corresponds to fraction of each nucleoside derivative (the prodrug diester, the parent free nucleoside, or monoesterified nucleoside) expressed as % of the initial diesterified prodrug concentration. HPLC determination used UV detection at 280 nm. Results are the mean ± s.e.m (std. error of mean) from three separate experiments
Scheme 1
Scheme 1
Synthesis of prodrugs of A3AR agonist. Reagents and conditions: (i) Procedure A. ROR, DMAP, Py, r.t.; Procedure B. RCl, DMAP, CH2Cl2, r.t.
Scheme 2
Scheme 2
Synthesis of prodrugs of A3AR antagonist. Reagents and conditions: (i) Procedure A. ROR, DMAP, Py, r.t.; Procedure B. RCl, DMAP, CH2Cl2, r.t.

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