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

A series of adenosine-5'-uronamide derivatives bearing N-6-phenylurea groups have been synthesized and tested for their affinity at A(1) and A(2A) adenosine receptors in rat brain membranes and at cloned rat A(3) receptors from stably transfected CHO cells. Some N-6-arylcarbamoyl derivatives, N-6-((2-chlorophenyl)carbamoyl)-, N-6-((3-chlorophenyl)carbarmoyl)-, and N-6-((4-methoxyphenyl)carbamoyl)adenosine-5'-ethyluronamide (41-n), were found to have affinity at A(3) receptors in the low nanomolar range (K-i values < 10 nM). In CHO cells stably transfected with the rat A(3) receptor, compound 4n was found to be a full agonist in inhibiting adenylate cyclase activity. The present study represents the first example of N-6-acyl-substituted adenosine analogs having high affinity at adenosine receptors and, in particular, at the A(3) receptor subtype.