Highly Selective Adenosine A2 Receptor Agonists in a Series of N-Alkylated 2-Aminoadenosines

Article abstract of DOI:10.1021/jm00112a035

A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A₂ receptor selective adenosine agonist 2-anilinoadenosine (CV-1808).High selectivity combined with significant affinity at the A₂ receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A₂ selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain.Some of these changes led to improved A₂ affinity and increased selectivity.Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A₂ site.These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.