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-β-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 (I; R = H, aryl-NHCO, heteroaryl-NHCO; R1 = aryl, aralkyl, aryl-NH, heteroaryl-NH; R2 = H, halo, alkynyl, aralkynyl) have been synthesized and tested for affinity at A1 and A2A adenosine receptors in rat brain membranes and at cloned rat A3 receptors expressed in CHO cells. The derivs. contained the 5' substituent found in the potent, nonselective agonist 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranuronamide (NECA). While the carboxamido derivs. I (R = H; R1 = aryl, aralkyl; R2 = H) showed affinity for A1 receptors, the urea derivs. I (R = H, aryl-NHCO, heteroaryl-NHCO; R1 = aryl, aralkyl, heteroaryl; R2 = H) showed different degrees of affinity and selectivity for the A3 adenosine receptor subtype. In particular the deriv. bearing a p-sulfonamidophenyl-urea at the 6 position, I (R = R2 = H, R1 = 4-NH2SO2C6H4NH) (II) showed a high affinity (Ki = 9 nM) and selectivity for the A3 receptors compared to that of the ref. compd. 1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-β-D-ribofuranuronamide (IB-MECA). Furthermore, the importance of the stereochem. in the interaction of these ligands at the rat A3 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 A2A and/or A3 receptors but rather showed a dramatic redn. of A2A affinity, resulting in compds. with good A2A/A3 selectivity. For example, the 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-6-(4-methoxyphenylurea) deriv. I [R = H, R1 = 4-MeOC6H4NH, R2 = PhCH(OH)C≡C] 61 showed the capability to bind simultaneously to A1 and A3 receptor subtypes, excluding the A2A receptor. Compd. II was shown to be an agonist, 9-fold more potent than NECA, at A3 receptors in rat RBL-2H3 mast cell membranes through stimulation of binding of [35S]GTP-γ-S.