NEW SUBSTITUTED 9-ALKYLPURINES AS ADENOSINE RECEPTOR LIGANDS

In the present study an investigation of the structure-activity relati onships in 9-ethylpurine derivatives, aimed at preparing A(1), A(2A), A(2B), and A(3) selective adenosine receptor antagonists, was undertak en. Our synthetic approach was to introduce various substituents (amin o, alkoxy and alkynyl groups) into the 2-, 6-, or 8-positions of the p urine ring. The starting compounds for each series of derivatives were respectively: 2-iodo-9-ethyladenine (9), obtained from 2-amino-6-chlo ropurine (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-ad enine (2). The synthesized compounds were tested in in vitro radioliga nd binding assays at A(1), A(2A), and A(3) human adenosine receptor su btypes. 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-ethylpur ine derivatives exhibited a similar pharmacological profile at A(1) an d 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 hig hest affinity in the series for the A(2A) and A(2B) subtypes (K-i = 0. 052 and 0.84 mu M, 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 affinit y at the As receptor (4d, K-i = 0.62 mu M), whereas (ar)alkynyl groups are detrimental for the potency at the A(2B) subtype. These differenc es give raise to the hope that further modifications will result in th e development of currently unavailable leads with good affinity and se lectivity for A(2B) adenosine receptors. (C) 1998 Elsevier Science Ltd . All rights reserved.