title: 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.
abstract: 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.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", Via D. Montesano, 49, 80131 Napoli, Italy. novellin.unima.it
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Marina
authors.initials: M
authors.lastname: Ehlardo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Manuela
authors.initials: M
authors.lastname: Iadanza
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rimoli
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sala
authors.forename: Antonio
authors.initials: A
authors.lastname: Da Settimo
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Primofiore
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Daniela
authors.initials: D
authors.lastname: Tuscano
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: 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
chemical_list: 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