Erythro- and threo-2-hydroxynonyl substituted 2-phenyladenines and 2-phenyl-8-azaadenines: ligands for A1 adenosine receptors and adenosine deaminase.
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.
Biagi
Giuliana
G
Department of Pharmaceutical Sciences, University of Pisa, Italy.
Giorgi
Irene
I
Livi
Oreste
O
Pacchini
Federica
F
Rum
Pietro
P
Scartoni
Valerio
V
Costa
Barbara
B
Mazzoni
Maria Rosa
MR
Giusti
Laura
L
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
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