title: Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A2AAdenosine Receptor Inverse Agonists with Antinociceptive Activity.
abstract: In this study, we describe the design and synthesis of new N5-substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A2Aadenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA2Areceptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA2AAR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, 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 degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Betti
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falsini
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Ravani
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D019342:Acetic Acid; D058908:Adenosine A2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000620288:2-(2-furanyl)thiazolo(5,4-d)pyrimidine-5,7-diamine; D058908:Adenosine A2 Receptor Agonists; D000700:Analgesics; D003959:Diamines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D013844:Thiazoles; D000242:Cyclic AMP; D019342:Acetic Acid