Prompted by pharmacophore and docking based models, we have synthesized and tested a number of N-alkyl and N-acyl-(7-substituted-2-phenylimidazo[1,2-a] [1,3,5]triazin-4-yl)amines (ITAs, 7) designed as a new class of A1 adenosine receptor (A1AR) antagonists. Binding affinities at the A1AR, A2AAR, and A3AR were determined using bovine cerebral membranes. Most of the compounds displayed Ki values at the A1AR in the submicromolar or even in the low nanomolar range, thus confirming the rationale leading to their synthesis. All or most of the ligands turned out to be selective for the A1AR over the A2AAR and A3AR subtypes, respectively. Structure-affinity relationships at the A1AR were rationalized by docking simulations in terms of putative ligand/receptor interactions. Among the ITAs investigated, 1-[(7-methyl-2-phenylimidazo [1,2-a][1,3,5]triazin-4-yl)amino] acetone (7j) exhibited the best combination of affinity at the A1AR (Ki = 12 nM) and selectivity over the A2AAR and A3AR subtypes (Kis > 10000 nM).
|Autori interni:||DA SETTIMO PASSETTI, FEDERICO|
TRINCAVELLI, MARIA LETIZIA
|Autori:||NOVELLINO E; ABIGNENTE E; COSIMELLI B; GRECO G; IADANZA M; LANERI S; LA VECCHIA A; RIMOLI MG; DA SETTIMO F; PRIMOFIORE G; TRINCAVELLI ML; MARTINI C|
|Titolo:||Design, Synthesis and Biological Evaluation of Novel N-Alkyl- and N-Acyl-(7-substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs) as Novel A(1) Adenosine Receptor Antagonists|
|Anno del prodotto:||2002|
|Digital Object Identifier (DOI):||10.1021/jm020911e|
|Appare nelle tipologie:||1.1 Articolo in rivista|