title: Further studies on pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective human A1 adenosine receptor antagonists.
abstract: A new series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays on human A1, A2A and A3 adenosine receptors. Most of the compounds showed high selectivity of action towards A1 receptor and high affinity with Ki values in the low nanomolar range. The pharmacological profile of the most active molecules towards A1 adenosine receptors was evaluated in cAMP functional assay. Compounds demonstrated their ability to completely counteract the effect of the agonist NECA, thus demonstrating their antagonist profile. Moreover, the most interesting compound, tested in the mouse passive avoidance, exhibited an antiamnesic effect at the doses of 10 and 30 mg/kg.
authors.affiliation: Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. Electronic address: mariapaola.giovannoni@unifi.it.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.affiliation: Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ciciani
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.affiliation: Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: NEUROFARBA, Sezione Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: NEUROFARBA, Sezione Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.affiliation: Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guerrini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D011724:Pyridazines; D043682:Receptor, Adenosine A1; C000600673:pyrazolo(1',5'-1,6)pyrimido(4,5-d)pyridazin-4(3H)-one
keywords: A(1) subtype; Human adenosine receptor; Pyrazolo[1′,5′:1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones; Selectivity