Abstract
In the present study an investigation of the structure-activity relationships
in 9-ethylpurine derivatives, aimed at preparing A1, A2A, A2B, and
A3 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-9H-purine (11), 8-bromo-9-ethyl-adenine (3) and
8-bromo-9-ethyl-6-iodo-9H-purine (13), obtained from 9-ethyl-adenine
(2). The synthesized compounds were tested in in vitro radioligand
binding assays at A1, A2A, and A3 human adenosine receptor subtypes.
Due to the lack of a suitable radioligand the affinity of the 9-ethyladenine
derivatives at A2B adenosine receptors was determined in adenylyl
cyclase experiments. In general, the series of 9-ethylpurine derivatives
exhibited a similar pharmacological profile at A1 and A2A receptors
whereas some differences were found for the A3 and the A2B 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 A2A and A2B subtypes (Ki = 0.052 and 0.84 microM,
respectively). Analyzing the different substituents, a phenethoxy
group in 2-position (10a) gave the highest A2A versus A2B selectivity
(near 400-fold), whereas a phenethylamino group in 2- and 6-position
(10b and 12b, respectively) improved the affinity at A2B 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 A3 receptor
(4d, Ki = 0.62 microM), whereas (ar)alkynyl groups are detrimental
for the potency at the A2B 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 A2B adenosine receptors.
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