2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists at human A(1) and A(3) adenosine receptors designed by 3D database searching.
The Cambridge Structural Database (CSD) was searched through two 3D queries based on substructures shared by well-known antagonists at the A(1) and A(3) adenosine receptors (ARs). Among the resulting 557 hits found in the CSD, we selected five compounds to purchase, synthesize, or translate synthetically into analogues better tailored to interact with the biological targets. Binding experiments using human ARs showed that four out of five tested compounds turned out to be antagonists at the A(1)AR or A(3)AR with K(i) values between 50 and 440 nM. Lead optimizations of 2-(benzimidazol-2-yl)quinoxalines (BIQs, 3) gave the best results in terms of potency and selectivity at the A(1) and A(3) ARs. Particularly, 2-(4-ethylthiobenzimidazol-2-yl)quinoxaline (3e) exhibited K(i) values at the A(1)AR, A(2A)AR, and A(3)AR of 0.5, 3440, and 955 nM, respectively, whereas 2-(4-methylbenzimidazol-2-yl)quinoxaline (3b) displayed at the same ARs K(i) values of 8000, 833, and 26 nM, respectively.
Novellino
Ettore
E
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", Via D. Montesano, 49, 80131 Napoli, Italy. novellin.unima.it
Cosimelli
Barbara
B
Ehlardo
Marina
M
Greco
Giovanni
G
Iadanza
Manuela
M
Lavecchia
Antonio
A
Rimoli
Maria Grazia
MG
Sala
Annalisa
A
Da Settimo
Antonio
A
Primofiore
Giampaolo
G
Da Settimo
Federico
F
Taliani
Sabrina
S
La Motta
Concettina
C
Klotz
Karl-Norbert
KN
Tuscano
Daniela
D
Trincavelli
Maria Letizia
ML
Martini
Claudia
C
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D058916:Adenosine A1 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism
D058916:Adenosine A1 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D001562:Benzimidazoles; D011810:Quinoxalines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D014970:Xanthines; D019830:Adenosine-5'-(N-ethylcarboxamide); C051360:1,3-dipropyl-8-cyclopentylxanthine; C089722:N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide; D000241:Adenosine