title: The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1and A2Areceptor affinity and selectivity profiles.
abstract: New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1and/or A2Areceptor subtypes. On the whole, the novel derivatives 1-24 shared scarce or no affinities for the off-target hA2Band hA3ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki= 150 nM) and the best selectivity for the hA2AAR while the 5-benzylamino-substituted 5 displayed the best combined hA2A(Ki= 123 nM) and A1AR affinity (Ki= 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki= 11 nM) and good selectivity for the hA1AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15-24 bind the hA1AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.[Formula: see text].
authors.affiliation: a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Squarcialupi
authors.affiliation: a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Betti
authors.affiliation: a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.affiliation: a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.affiliation: a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falsini
authors.affiliation: b Dipartimento di Scienze Mediche, Sezione di Farmacologia , Università di Ferrara , Ferrara , Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Ravani
authors.affiliation: b Dipartimento di Scienze Mediche, Sezione di Farmacologia , Università di Ferrara , Ferrara , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pasquini
authors.affiliation: b Dipartimento di Scienze Mediche, Sezione di Farmacologia , Università di Ferrara , Ferrara , Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: c Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco , Università di Padova , Padova , Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Salmaso
authors.affiliation: c Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco , Università di Padova , Padova , Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Sturlese
authors.affiliation: b Dipartimento di Scienze Mediche, Sezione di Farmacologia , Università di Ferrara , Ferrara , Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.affiliation: c Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco , Università di Padova , Padova , Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.affiliation: a Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università di Firenze , Sesto Fiorentino , Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; C027179:7-aminopyrazolo(4,3-d)pyrimidine
keywords: Adenosine A1 and A2A receptor antagonists; G protein-coupled receptors; ligand-receptor modeling studies; pyrazolo[4,3-d]pyrimidines