2,8-Disubstituted adenosine derivatives as partial agonists for the adenosine A2A receptor Original Research Article

Novel 2,8-disubstituted adenosine derivatives were synthesized in good overall yields starting from 2-iodoadenosine. Binding affinities were determined for rat adenosine A1 and A2A receptors and human A3 receptors. Some compounds displayed good adenosine A2A receptor affinities, with most of the 2-(1-hexynyl)- and 2-[(E)-1-hexenyl]-substituted derivatives having Ki values in the nanomolar range. Although the introduction of an 8-alkylamino substituents decreased the affinity for the adenosine A2A receptor somewhat, the selectivity for this receptor compared to A3 was improved significantly. The 8-methylamino (12) and 8-propylamino (14) derivatives of 2-(1-hexynyl)adenosine (3), showed reasonable A2A receptor affinities with Ki values of 115 and 82 nM, respectively, and were 49- and 26-fold selective for the adenosine A2A receptor compared to the A3 receptor. The compounds were also evaluated for their ability to stimulate the cAMP production in CHO cells expressing the human adenosine A2A receptor. 2-(1-Hexynyl)adenosine (3) and 2-[(E)-1-hexenyl]adenosine (4) both showed submaximal levels of produced cAMP, compared to the reference full agonist CGS 21680, and thus behaved as partial agonists. Most 8-alkylamino-substituted derivatives of 3, displayed similar cAMP production as 3, and behaved as partial agonists as well. Introduction of alkylamino groups at the 8-position of 4, showed a slight reduction of the efficacy compared to 4, and these compounds were partial agonists also.