title: New N6- or N(9)-hydroxyalkyl substituted 8-azaadenines or adenines as effective A1 adenosine receptor ligands.
abstract: 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).
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, I-56126, Pisa, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Biagi
authors.forename: Irene
authors.initials: I
authors.lastname: Giorgi
authors.forename: Michele
authors.initials: M
authors.lastname: Leonardi
authors.forename: Oreste
authors.initials: O
authors.lastname: Livi
authors.forename: Federica
authors.initials: F
authors.lastname: Pacchini
authors.forename: Valerio
authors.initials: V
authors.lastname: Scartoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D001372:Aza Compounds; D008024:Ligands; D043682:Receptor, Adenosine A1; D014867:Water; D000225:Adenine