2-Aralkynyl and 2-heteroalkynyl derivatives of adenosine-5'-N-ethyluronamide as selective A2a adenosine receptor agonists.

A series of new 2-aralkynyl and 2-heteroaralkynyl derivatives of NECA were synthesized and studied in binding and functional assays to assess their potency for the A(2a) compared to A(1) adenosine receptors. Compounds bearing an aromatic or heteroaromatic ring, conjugated to the triple bond, showed generally weaker activity at the A(2a) receptor and lower selectivity (A(2a) vs A(1)) than the alkylalkynyl derivatives previously reported. However, the (4-formylphenyl)ethynyl derivative 17 showed affinity in the low nanomolar range and high selectivity (about 160-fold) for the A(2a) receptor. The presence of heteroatoms improved vasorelaxant activity, the 2-thiazolylethynyl derivative 30 being the most potent in the series. Introduction of methylene groups between the triple bond and the phenyl ring favored the A(2a) binding affinity, and the 5-phenyl-1-pentynyl derivative 24 was found to be highly potent and selective (about 180-fold) at A(2a) receptors. With regard to antiplatelet activity, the presence of aromatic or heteroaromatic rings decreased potency in comparison with that of NECA and of N-ethyl-1'deoxy-1'-(6-amino-2-hexynyl-9H-purin-9-yl)-beta-D-ribofuranuronamide (HENECA). Introduction of a methylene group was effective in increasing antiaggregatory potency only when this group is linked to a heteroatom (31-35). From these data and those previously reported, the structure-activity relationships derived for the 2-alkynyl-substituted ribose uronamides would indicate that potentiation of A(2a) receptor affinity could be obtained by aromatic rings not conjugated with the triple bond or by heteroaromatic groups. As for A(2a) receptors on platelets, the presence of aromatic rings, either conjugated or unconjugated to the triple bond, is detrimental for the antiaggregatory activity. However, the introduction of polar groups alpha to the triple bond strongly increases the potency when steric hindrance is avoided. Some of the compounds included in this series retain interesting vasodilating properties and merit further investigation for their potential in the treatment of cardiovascular disorders.