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.
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).
Novellino
Ettore
E
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno 6, Italy. novellin@unina.it
Abignente
Enrico
E
Cosimelli
Barbara
B
Greco
Giovanni
G
Iadanza
Manuela
M
Laneri
Sonia
S
Lavecchia
Antonio
A
Rimoli
Maria Grazia
MG
Settimo
Federico Da
FD
Primofiore
Giampaolo
G
Tuscano
Daniela
D
Trincavelli
Letizia
L
Martini
Claudia
C
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
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