Synthesis and biological activity of a new series of N6-arylcarbamoyl, 2-(Ar)alkynyl-N6-arylcarbamoyl, and N6-carboxamido derivatives of adenosine-5′-N-ethyluronamide as A1 and A3 adenosine receptor agonists

A new series of 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide-bearing N-arylureas or N-arylcarboxamido groups at the purine 6 position and N-arylureas combined with halogens Or alkynyl chains at the 2 position have been synthesized and tested for affinity at A(1) and A(2A) adenosine receptors in rat brain membranes and at cloned rat A(3) receptors expressed in CHO cells. The derivatives contained the 5' substituent found in the potent, nonselective agonist 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide (NECA). While the carboxamido derivatives (9-13) showed affinity for A(1) receptors, the urea derivatives (30-45) showed different degrees of affinity and selectivity for the A(3) adenosine receptor subtype. In particular the derivative bearing a p-sulfonamidophenyl-urea at the 6 position, 31 showed a high affinity (K-i = 9 nM) and selectivity for the A(3) receptors compared to that of the reference compound 1-[6 -[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide (IB-MEGA). Furthermore, the importance of the stereochemistry in the interaction of these ligands at the rat A(3) adenosine receptors has been evaluated by introducing a chiral chain at the 6 position. The introduction of halogens or alkynyl chains at the purine 2 position of selected ureas did not give the expected enhancement of potency at A(2A) and/or A(3) receptors but rather showed a dramatic reduction of A(2A) affinity, resulting in compounds with good A(2A)/A(3) selectivity. For example, the 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-6-(4-methoxyphenylurea) derivative 61 showed the capability to bind simultaneously to A(1) and A(3) receptor subtypes, excluding the A2A receptor. Compound 31 was shown to be an agonist, 9-fold more potent than NECA, at A(3) receptors in rat RBL-2H3 mast cell membranes through stimulation of binding of [S-35]GTP-gamma-S.