New N6- or N(9)-hydroxyalkyl substituted 8-azaadenines or adenines as effective A1 adenosine receptor ligands

In this paper we describe synthesis and biological assays of some A(1) ligands more water-soluble than the effective, but very lipophilic, 8-azaadenines and adenines discovered in the past and obtained introducing on N(6) or N(9) substituent a hydroxy group. Five of the new N(6)-hydroxyalkyl- and N(6)-hydroxycycloalkyl-2-phenyl-9-benzyl-8-azaadenines showed very high affinity (Ki<40 nM) and selectivity for A(1) adenosine receptors. Among the 2-phenyl-9-(2-hydroxy-3-alkyl)-8-azaadenines or adenines prepared, the compounds with the higher A(1) affinity and selectivity resulted 2-phenyl-9-(2-hydroxy-3-propyl)-N(6)-cyclopentyl- and cyclohexyl-8-azaadenine with Ki 2.2+/-0.2 nM and 2.8+/-0.3 nM respectively. From the point of view of water-solubility, 2-phenyl-9-(2-hydroxy-3-propyl)-8-azaadenine was the most interesting compound, having a CLogP of 1.066991 and a water-solubility of 1.2 mg mL(-1).