title: 1,2,4-triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A₃ receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies.
abstract: The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy. Electronic address: daniela.catarzi@unifi.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Poli
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Squarcialupi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Betti
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Trincavelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011810:Quinoxalines
keywords: Adenosine receptor antagonists; G protein-coupled receptors; Ligand–receptor modeling studies; Triazoloquinoxalines; Tricyclic heteroaromatic systems