2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamide as selective agonists at A2 adenosine receptors

Article abstract of DOI:10.1021/jm00091a003

In the search for more selective A₂-receptor agonists and on the basis that appropriate substitution at C2 is known to impart selectivity for A₂ receptors, 2-alkynyladenosines 2a-d were resynthesized and evaluated in radioligand binding, adenylate cyclase, and platelet aggregation studies. Binding of [³H]NECA to A₂ receptors of rat striatal membranes was inhibited by compounds 2a-d with K(i) values ranging from 2.8 to 16.4 nM. 2- Alkynyladenosines also exhibited high-affinity binding at solubilized A₂ receptors from human platelet membranes. Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand [³H]DPCPX and for the agonist [³H]CCPA gave K(i) values in the nanomolar range, and the compounds showed moderate A₂ selectivity. In order to improve this selectivity, the corresponding 2- alkynyl derivatives of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested. As expected, the 5'-N-ethyluronamide derivatives retained the A₂ affinity whereas the A₁ affinity was attenuated, resulting in an up to 10- fold increase in A₂ selectivity. A similar pattern was observed in adenylate cyclase assays and in platelet aggregation studies. A 30- to 45-fold selectivity for platelet A₂ receptors compared to A₁ receptors was found for compounds 8a-c in adenylate cyclase studies.