8-ALKENYL AND 8-ALKYL DERIVATIVES OF ADENOSINE AND ADENOSINE-5'-N-ETHYLURONAMIDE - DIFFERENT AFFINITY AND SELECTIVITY OF E-DIASTEREOMER ANDZ-DIASTEREOMER AT A(2A) ADENOSINE RECEPTORS

A series of new 2-(ar)alkenyl, both Z- and E-diastereomers, and 2-alky l derivatives of adenosine-5'-N-ethyluronamide (NECA) and adenosine we re synthesized and evaluated for their interaction with the A(1) and A (2A) adenosine receptors, to better understand the conformational requ irements of the receptor area interacting with the substituents in the 2- and 5'-positions. Partial reduction of the triple bond in 2-alkyny l derivatives of NECA led to compounds whose activity at the A(2A) rec eptor subtype was related to Z-E-isomerism, the E-diastereomers being more potent and selective than the Z-ones. Saturation of the side chai n markedly reduced compound affinity at adenosine receptors. Specifica lly, compounds bearing an (E)-alkenyl chain, while maintaining the sam e affinity at A(2A) receptors as the corresponding alkynyl derivatives , showed an increase in A(2A) vs A(1) selectivity. Hence, the new nucl eosides (E)-2-hexenylNECA (12a) and (E)-2-(phenylpenteny1)NECA (12b) e xhibited both high A(2A) receptor affinity (K-i = 1.6 and 3.5 nM, resp ectively) and A(2A) VS A(1) selectivity (157- and 290-fold, respective ly). Moreover, 12a displayed potent antiaggregatory activity, similar to that of the reference compound NECA. Comparison between NECA and ad enosine derivatives further demonstrated that the 5'-ethylcarboxamido group is critical for the A(2A) affinity. These studies indicated that the orientation of the substituent in the 2-position and the nature o f the 5'-group in adenosine derivatives are critical to achieve high a ffinity and selectivity at the A(2A) adenosine receptor subtype.