Novel N-6-(substituted-phenylcarbamoyl)adenosine-5'-uronamides as potent agonists for A(3) adenosine receptors

Title compds. I (R = Et, R1 = H, CF3, MeO, F, Cl, I, 4-​Me, 3-​Br; R = Me, R1 = 4-​MeO, 3-​Cl) were synthesized and tested for their affinity at A1 and A2A adenosine receptors in rat brain membranes and at cloned rat A3 receptors from stably transfected CHO cells. N6-​[(2-​chlorophenyl)​carbamoyl]​-​, N6-​[(3-​chlorophenyl)​carbamoyl]​-​, and N6-​[(4-​methoxyphenyl)​carbamoyl]​adenosine-​5'-​ethyluronamide (II) had affinity at A3 receptors in the low nanomolar range (Ki values <10 nM)​. In CHO cells stably transfected with the rat A3 receptor, II was a full agonist in inhibiting adenylate cyclase activity. The present study represents the first example of N6-​acyl-​substituted adenosine analogs having high affinity at adenosine receptors and, in particular, at the A3 receptor subtype.