Bioisosterism, enantioselectivity, and molecular modeling of new effective N6‐ and/or N(9)‐substituted 2‐phenyl adenines and 8‐aza analogs: Different binding modes to A1 adenosine receptors

Bioisosterism of the adenine and 8‐azaadenine nuclei was demonstrated by comparison of A1 adenosine receptor binding affinity of 2‐phenyl N6‐substituted adenines and the corresponding 8‐azaadenines. Some of these new compounds are very potent A1 adenosine receptor antagonists. This work also describes the synthesis and A1 adenosine receptor binding of the enantiomers of some 2‐phenyladenines substituted with a 1‐phenylethyl chiral group in N6 and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2‐phenylsubstituted adenines inside A1 adenosine receptors. Theoretical studies, based on an improved A1 adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52–65, 2001.