Structure-Activity Relationships of N⁶-Benzyladenosine-5′-uronamides as A₃-Selective Adenosine Agonists

Adenosine analogues modified at the 5′-position as uronamides and/or as N⁶ benzyl derivatives were synthesized. These derivatives were examined for affinity in radioligand binding assays at the newly discovered rat brain A₃ adenosine receptor and at rat brain and A₁ and A_2a receptors. 5′- Uronamide substituents favored A₃ selectivity in the order N-methyl > N-ethyl ≈ unsubstituted carboxamide > N-cyclopropyl. 5′-(N-Methylcarboxamido)-N⁶ benzyladenosine was 37–56-fold more selective for A₃ receptors. Potency at A₃ receptors was enhanced upon substitution of the benzyl substituent with nitro and other groups. 5′-N-Methyluronamides and N⁶(3-substitutedbenzyl) adenosines are optimal for potency and selectivity at A₃ receptors. A series of 3-(halobenzyl)- 5′-N-ethyluronamide derivatives showed the order of potency at A₁ and A_2a receptors of I ∼ Br > Cl > F. At A₃ receptors the 3-F derivative was weaker than the other halo derivatives. 5′-N-Methyl-N⁶-(3-iodobenzyl)adenosine displayed a K_i, value of 1.1 nM at A₃ receptors and selectivity versus A1₁ and A_2a receptors of 50-fold. A series of methoxybenzyl derivatives showed that a 4-methoxy group best favored A₃ selectivity. A 4-sulfobenzyl derivative was a specific ligand at A₃ receptors of moderate potency. An aryl amino derivative was prepared as a probe for radioiodination and receptor cross-linking.