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

Article abstract of DOI:10.1021/jm00031a014

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 A₁ and A_2a receptors. 5'-Uronamide substituents favored A₃ selectivity in the order N-methyl > N-ethyl ca. 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 ca.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 A₁ 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.