SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A NEW SERIES OF N-6-ARYLCARBAMOYL, 2-(AR)ALKYNYL-N-6-ARYLCARBAMOYL, AND N-6-CARBOXAMIDO DERIVATIVES OFADENOSINE-5'-N-ETHYLURONAMIDE AS A(1) AND A(3) ADENOSINE RECEPTOR AGONISTS

A new series of -1-deoxy-N-ethyl-beta-D-ribofuranuronamide-bearing N-a rylureas or N-arylcarboxamido groups at the purine 6 position and N-ar ylureas combined with halogens Or alkynyl chains at the 2 position hav e 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 exp ressed in CHO cells. The derivatives contained the 5' substituent foun d in the potent, nonselective agonist in-9-yl)-1-deoxy-N-ethyl-beta-D- ribofuranuronamide (NECA). While the carboxamido derivatives (9-13) sh owed affinity for A(1) receptors, the urea derivatives (30-45) showed different degrees of affinity and selectivity for the A(3) adenosine r eceptor subtype. In particular the derivative bearing a p-sulfonamidop henyl-urea at the 6 position, 31 showed a high affinity (K-i = 9 nM) a nd selectivity for the A(3) receptors compared to that of the referenc e compound 1-[6 n-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide (IB -MEGA). Furthermore, the importance of the stereochemistry in the inte raction of these ligands at the rat A(3) adenosine receptors has been evaluated by introducing a chiral chain at the 6 position. The introdu ction of halogens or alkynyl chains at the purine 2 position of select ed 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) aff inity, resulting in compounds with good A(2A)/A(3) selectivity. For ex ample, the xy-3-phenyl-1-propyn-1-yl)-6-(4-methoxyphenylurea) derivati ve 61 showed the capability to bind simultaneously to A(1) and A(3) re ceptor 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]GT P-gamma-S.