title: 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.
abstract: 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 A(1) adenosine receptor (A(1)AR) antagonists. Binding affinities at the A(1)AR, A(2A)AR, and A(3)AR were determined using bovine cerebral membranes. Most of the compounds displayed K(i) values at the A(1)AR 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 A(1)AR over the A(2A)AR and A(3)AR subtypes, respectively. Structure-affinity relationships at the A(1)AR 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 A(1)AR (K(i) = 12 nM) and selectivity over the A(2A)AR and A(3)AR subtypes (K(i)s > 10000 nM).
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno 6, Italy. novellin@unina.it
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Enrico
authors.initials: E
authors.lastname: Abignente
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Manuela
authors.initials: M
authors.lastname: Iadanza
authors.forename: Sonia
authors.initials: S
authors.lastname: Laneri
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rimoli
authors.forename: Federico Da
authors.initials: FD
authors.lastname: Settimo
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Primofiore
authors.forename: Daniela
authors.initials: D
authors.lastname: Tuscano
authors.forename: Letizia
authors.initials: L
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C468790:1-((7-methyl-2-phenylimidazo(1,2-a)(1,3,5)triazin-4-yl)amino)acetone; D007093:Imidazoles; D058915:Purinergic P1 Receptor Antagonists; D014227:Triazines