Novel N6-(substituted-phenylcarbamoyl)adenosine-5'-uronamides as potent agonists for A3 adenosine receptors

Abstract

A series of adenosine-5'-uronamide derivatives bearing N6-phenylurea groups have been 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. Some N6-arylcarbamoyl derivatives, N6-((2-chlorophenyl)carbamoyl)-, N6-((3-chlorophenyl)carbamoyl)-, and N6-((4-methoxyphenyl)carbamoyl)adenosine-5'-ethyluronamide (4l-n), were found to have affinity at A3 receptors in the low nanomolar range (Ki values < 10 nM). In CHO cells stably transfected with the rat A3 receptor, compound 4n was found to be 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.

Figure 1.

Inhibition of adenylate cyclase by the adenosine derivative N⁶-((3-chlorophenyl)carbamoyl)adenosine-5′-ethyluronamide, 4n, in membranes from CHO cell stably transfected with rat A₃ receptors. The assay was carried out as described in the Experimental Section in the presence of 1 μM forskolin. Each data point is shown as mean ± SEM for three determinations. The IC₅₀ value was 0.85 ± 0.14 μM.

Scheme 1