title: Synthesis and structure-activity relationships of 4-cycloalkylamino-1, 2, 4-triazolo[4, 3-a]quinoxalin-1- one derivatives as A1 and A3 adenosine receptor antagonists.
abstract: In a previous paper we reported the synthesis and binding activity of 4-cycloalkylamino-1, 2, 4-triazolo[4, 3-a]quinoxalin-1-one derivatives, differently substituted on the appended 2-phenyl ring, some of which were potent and selective A(1) adenosine receptor (AR) antagonists. In the present paper several 4-cycloalkylamino-2-phenyl-1, 2, 4-triazolo[4, 3-a]quinoxalin-1-one derivatives (1-11), bearing simple substituents on the benzofused moiety, are reported. The binding data of bovine A(1) and A(2A) and human A(3) AR show that we have obtained highly potent A(1) AR antagonists. In particular, the 4-cyclohexylamino derivatives 1-5 show higher A(1) vs A(2A) selectivity than the parent compound A, which lacks substituents on the benzofused moiety. Moreover, compounds 1-11 display, in general, good A(3) AR affinity. Finally, SAR studies provide some new insights about the steric requirements of the A(3) receptor pocket, which accommodates the benzofused moiety of our 4-amino-triazoloquinoxalin-1-one derivatives.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, Firenze, Italy. vittoria.colotta@unifi.it
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Letizia
authors.initials: L
authors.lastname: Trincavelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D000473:Alkanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002417:Cattle; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007456:Iodine Isotopes; D008566:Membranes; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D010627:Phenethylamines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D058914:Purinergic Antagonists; D021281:Quantitative Structure-Activity Relationship; D011810:Quinoxalines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011983:Receptors, Purinergic / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014316:Tritium
chemical_list: D000473:Alkanes; D007456:Iodine Isotopes; D010627:Phenethylamines; D058914:Purinergic Antagonists; D011810:Quinoxalines; D011983:Receptors, Purinergic; D014230:Triazoles; D014316:Tritium; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C027513:N(6)-cyclohexyladenosine; C089722:N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide; D000241:Adenosine