New substituted 9-alkylpurines as adenosine receptor ligands

Abstract

In the present study an investigation of the structure–activity relationships in 9-ethylpurine derivatives, aimed at preparing A 1, A 2A, A 2B, and A 3 selective adenosine receptor antagonists, was undertaken. Our synthetic approach was to introduce various substituents (amino, alkoxy and alkynyl groups) into the 2-, 6-, or 8-positions of the purine ring. The starting compounds for each series of derivatives were respectively: 2-iodo-9-ethyladenine ( 9), obtained from 2-amino-6-chloropurine ( 5); 9-ethyl-6-iodo-9 H-purine ( 11), 8-bromo-9-ethyl-adenine ( 3) and 8-bromo-9-ethyl-6-iodo-9 H-purine ( 13), obtained from 9-ethyl-adenine ( 2). The synthesized compounds were tested in in vitro radioligand binding assays at A 1, A 2A, and A 3 human adenosine receptor subtypes. Due to the lack of a suitable radioligand the affinity of the 9-ethyladenine derivatives at A 2B adenosine receptors was determined in adenylyl cyclase experiments. In general, the series of 9-ethylpurine derivatives exhibited a similar pharmacological profile at A 1 and A 2A receptors whereas some differences were found for the A 3 and the A 2B subtypes. 8-Bromo-9-ethyladenine ( 3) showed higher affinity for all receptors in comparison to the parent compound 2, and the highest affinity in the series for the A 2A and A 2B subtypes ( K i=0.052 and 0.84 μM, respectively). Analyzing the different substituents, a phenethoxy group in 2-position ( 10a) gave the highest A 2A versus A 2B selectivity (near 400-fold), whereas a phenethylamino group in 2- and 6-position ( 10b and 12b, respectively) improved the affinity at A 2B receptors, compared to the parent compound 2. The presence of a hexynyl substituent in 8-position led to a compound with good affinity at the A 3 receptor ( 4d, K i=0.62 μM), whereas (ar)alkynyl groups are detrimental for the potency at the A 2B subtype. These differences give raise to the hope that further modifications will result in the development of currently unavailable leads with good affinity and selectivity for A 2B adenosine receptors.