title: Erythro- and threo-2-hydroxynonyl substituted 2-phenyladenines and 2-phenyl-8-azaadenines: ligands for A1 adenosine receptors and adenosine deaminase.
abstract: erythro-2-Phenyl-9-(2-hydroxy-3-nonyl)adenine and its 8-aza analog were prepared and showed a very high inhibitory activity towards adenosine deaminase (ADA), with Ki 0.55 and 1.67 nM, respectively, and high affinity for A1 adenosine receptors, with Ki 28 and 2.8 nM, respectively. To increase affinity for A1 receptors we introduced a substituent on the N6 position such as alkyl or cycloalkyl groups, which are present in effective agonists or antagonists. Furthermore, for some compounds, we prepared the two diastereoisomers erythro and threo to verify whether the binding with A1 receptors is stereoselective, as in ADA. Results show that some of the synthesised compounds are good inhibitors for ADA and good ligands for A1, and the erythro diastereoisomers are more active than the threo ones. The experimental evidence allows us to hypothesise some similarity in the three dimensional structures of the binding site of the two proteins, ADA and A1 adenosine receptor, in spite of lacking any homologies in the amino acid sequences.
authors: Department of Pharmaceutical Sciences, University of Pisa, Italy.
authors: Giuliana
authors: G
authors: Biagi
authors: Irene
authors: I
authors: Giorgi
authors: Oreste
authors: O
authors: Livi
authors: Federica
authors: F
authors: Pacchini
authors: Pietro
authors: P
authors: Rum
authors: Valerio
authors: V
authors: Scartoni
authors: Barbara
authors: B
authors: Costa
authors: Maria Rosa
authors: MR
authors: Mazzoni
authors: Laura
authors: L
authors: Giusti
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D017072:Neostriatum / Q000378:metabolism; D011869:Radioligand Assay; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D058892:Adenosine Deaminase Inhibitors; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D008024:Ligands; D018047:Receptors, Purinergic P1; C010192:9-(2-hydroxy-3-nonyl)adenine; D000225:Adenine; C006654:8-azaadenine