N6-substituted C5′-modified adenosines as A1 adenosine receptor agonists

Abstract: Adenosines bearing 5′-modification in conjunction with an N6-substituent have previously been shown to act as partial agonists at the A1 adenosine receptor. Our current work investigates the effect of modifying the 5′-position in conjunction with efficacious bicyclic and tricyclic N6-substituents. Several highly potent agonists for the A1 adenosine receptor were identified; however, all of these compounds behaved as full agonists. In keeping with previous reports, 5′-halogen and 5′-sulfide derivatives of N 6-(endo-norborn-2-yl)adenosine were, in general, low nanomolar agonists of the A1 adenosine receptor. The known partial agonist, N 6-cyclopentyl-5′-deoxy-5′-ethylthioadenosine (2), also behaved as a full agonist in our assay. [Copyright &y& Elsevier]