Nucleosides and Nucleotides. 112. 2-(1-Hexyn-1-yl)adenosine-5'-uronamides: A New Entry of Selective A2 Adenosine Receptor Agonists with Potent

Article abstract of DOI:10.1021/jm00093a022

Chemical modifications of the potent A₂ adenosine receptor agonist 2-(1-hexyn-1-yl)adenosine (7, 2-HA) at the 5'-position have been carried out to find more potent and selective A₂ agonists. these analogues were evaluated for adenosine A₁ and A₂ receptor binding affinity in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR).Among the series of compounds, 2-(1-hexyn-1-yl)adenosine-5'-N-cyclopropyluronamide (16d) had the most potent affinity to the A₂ receptor with a K_i of 2.6 nM, which is essentially the same as that of the parent agonist, 2-HA.However, the most selective agonist for the A₂ receptor was 2-(1-hexyn-1-yl)adenosine-5'-N-methyluronamide (16b) with a K_i of 11 nM and a 162-fold selectivity.The N-alkyl substituents of 5'-uronamide derivatives did not seem to potentiate the A₂ binding affinity but drastically reduced the A₁ affinity compared with the parent 2-HA.Therefore, the A₁/A₂ selectivity was consequently increased.Other 5'-deoxy-5'-substituted derivatives of 2-HA such as the chloro (20), carboxamide (27, 28), sulfonamide (29), urea (30), and thiourea (22) analogues were also prepared.Among these nucleosides, no active compounds with potent or selective affinities to both receptors were found except 20.Although glycosyl conformations and sugar-puckering of these nucleosides were studied by 1H NMR spectroscopy, there were no positive correlations between active and inactive agonists. 2-(1-Hexyn-1-yl)adenosine-5'-uronamide (16a) and 16d had a potent hypotensive effect at ED₃₀ values of 0.18 and 0.17 μg/kg, respectively, upon iv administration to anesthetized SHR.