title: Exploring the 7-oxo-thiazolo[5,4-d]pyrimidine core for the design of new human adenosine A3 receptor antagonists. Synthesis, molecular modeling studies and pharmacological evaluation.
abstract: A new series of 5-methyl-thiazolo[5,4-d]pyrimidine-7-ones bearing different substituents at position 2 (aryl, heteroaryl and arylamino groups) was synthesized and evaluated in radioligand binding assays to determine their affinities at the human (h) A1, A2A, and A3 adenosine receptors (ARs). Efficacy at the hA(2B) and antagonism of selected ligands at the hA3 were also assessed through cAMP experiments. Some of the new derivatives exhibited good to high hA3AR affinity and selectivity versus all the other AR subtypes. Compound 2-(4-chlorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidine-7-one 4 was found to be the most potent and selective ligand of the series (K(I) hA3 = 18 nM). Molecular docking studies of the reported derivatives were carried out to depict their hypothetical binding mode in our hA3 receptor model.
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy. Electronic address: flavia.varano@unifi.it.
authors: Flavia
authors: F
authors: Varano
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors: Daniela
authors: D
authors: Catarzi
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors: Lucia
authors: L
authors: Squarcialupi
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors: Marco
authors: M
authors: Betti
authors: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Universita' di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors: Fabrizio
authors: F
authors: Vincenzi
authors: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Universita' di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors: Annalisa
authors: A
authors: Ravani
authors: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Universita' di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors: Katia
authors: K
authors: Varani
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, MC, Italy.
authors: Diego
authors: D
authors: Dal Ben
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, MC, Italy.
authors: Ajiroghene
authors: A
authors: Thomas
authors: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, MC, Italy.
authors: Rosaria
authors: R
authors: Volpini
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
authors: Vittoria
authors: V
authors: Colotta
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000606769:7-oxo-thiazolo(5,4-d)pyrimidine; D058918:Adenosine A3 Receptor Antagonists; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D013844:Thiazoles
keywords: Adenosine receptor antagonists; Bicyclic heteroaromatic systems; G protein-coupled receptors; Ligand-receptor modeling studies; Thiazolopyrimidine