5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: a versatile scaffold to obtain potent and selective A3 adenosine receptor antagonists.
Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previously reported as ligands at the central benzodiazepine receptor (BzR), possess nanomolar affinity at the A3 AR. Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-ones IX, which maintain a nanomolar potency at the A3 AR with selectivity over the BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1, A2A, and A2B ARs. The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one (23), which displayed a Ki of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level.
Da Settimo
Federico
F
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Primofiore
Giampaolo
G
Taliani
Sabrina
S
Marini
Anna Maria
AM
La Motta
Concettina
C
Simorini
Francesca
F
Salerno
Silvia
S
Sergianni
Valentina
V
Tuccinardi
Tiziano
T
Martinelli
Adriano
A
Cosimelli
Barbara
B
Greco
Giovanni
G
Novellino
Ettore
E
Ciampi
Osele
O
Trincavelli
Maria Letizia
ML
Martini
Claudia
C
D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C525467:9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl(1,2,3)triazolo(1,2-a)(1,2,4)benzotriazin-1-one; D058918:Adenosine A3 Receptor Antagonists; D014227:Triazines; D014230:Triazoles; D000242:Cyclic AMP