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-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 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 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 affinity 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 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.

New substituted 9-alkylpurines as adenosine receptor ligands

CAMAIONI, Emidio;
1998

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-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 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 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 affinity 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 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.
1998
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/906708
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