2-Alkenyl and 2-alkyl derivatives of adenosine and adenosine-5'-N-ethyluronamide: different affinity and selectivity of E- and Z-diastereomers at A2A adenosine receptors.

A series of new 2-(ar)alkenyl,both Z- and E-diastereomers,and 2-alkyl derivatives of adenosine-5'-N-ethyluronamide (NECA) and adenosine were synthesized and evaluated for their interaction with the A(1) and A(2A) adenosine receptors,to better understand the conformational requirements of the receptor area interacting with the substituents in the 2- and 5'-positions. Partial reduction of the triple bond in 2-alkynyl derivatives of NECA led to compounds whose activity at the A(2A) receptor subtype was related to Z-E-isomerism,the E-diastereomers being more potent and selective than the Z-ones. Saturation of the side chain markedly reduced compound affinity at adenosine receptors. Specifically,compounds bearing an (E)-alkenyl chain,while maintaining the same affinity at A(2A) receptors as the corresponding alkynyl derivatives,showed an increase in A(2A) vs A(1) selectivity. Hence,the new nucleosides (E)-2-hexenylNECA (12a) and (E)-2-(phenylpenteny1)NECA (12b) exhibited both high A(2A) receptor affinity (K-i = 1.6 and 3.5 nM,respectively) and A(2A) VS A(1) selectivity (157- and 290-fold,respectively). Moreover,12a displayed potent antiaggregatory activity,similar to that of the reference compound NECA. Comparison between NECA and adenosine 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 of the 5'-group in adenosine derivatives are critical to achieve high affinity and selectivity at the A(2A) adenosine receptor subtype.