title: Pyrazolo[1,5-c]quinazoline derivatives and their simplified analogues as adenosine receptor antagonists: synthesis, structure-affinity relationships and molecular modeling studies.
abstract: A number of 5-oxo-pyrazolo[1,5-c]quinazolines (series B-1), bearing at position-2 the claimed (hetero)aryl moiety (compounds 1-8) but also a carboxylate group (9-14), were designed as hA(3) AR antagonists. This study produced some interesting compounds endowed with good hA(3) receptor affinity and high selectivity, being totally inactive at all the other AR subtypes. In contrast, the corresponding 5-ammino derivatives (series B-2) do not bind or bind with very low affinity at the hA(3) AR, the only exception being the 5-N-benzoyl compound 19 that shows a hA(3)K(i) value in the high μ-molar range. Evaluation of the synthetic intermediates led to the identification of some 5(3)-(2-aminophenyl)-3(5)-(hetero)arylpyrazoles 20-24 with modest affinity but high selectivity toward the hA(3) AR subtype. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA(3) receptor.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy. daniela.catarzi@unifi.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Daniela
authors.initials: D
authors.lastname: Poli
authors.forename: Lucia
authors.initials: L
authors.lastname: Squarcialupi
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D056004:Molecular Dynamics Simulation; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011799:Quinazolines; D043684:Receptor, Adenosine A3