Molecular modeling of 2-alkyloxy- and 2-aralkyloxy-adenosine A1- and A2-agonists.

The C2-region of adenosine A1- and A2-receptors by a molecular modeling technique has been extended and applied to a series of 2-substituted adenosines reported by Olsson, et al. The similarity and dissimilarity of the structure maps obtained by molecular modeling have been used as a basis for the mapping of the analysed receptor domain. The proposed model of the C2-region of the A1-receptor consists of a narrow and sterically limited area that interacts well electrostatically with small and electron rich moieties. Olsson's provisional model of the C2-region of the A2-receptor has been extended with two subsites, as well as with a forbidden area near the C2-position of the purine ring. The conformational analysis performed in the study does not support the hypothesis of Olsson et al. that adenosine C2 substituents may partly occupy the same receptor domain as the N6 substituents of the A1-receptor. The occupation of the cycloalkyl subsite increases the receptor selectivity while the occupation of the other subsite by aryl rings, fixed at a parallel position to the purine system, highly enhances the receptor affinity.