title: Design, synthesis, and biological evaluation of novel 2-((2-(4-(substituted)phenylpiperazin-1-yl)ethyl)amino)-5'-N-ethylcarboxamidoadenosines as potent and selective agonists of the A2A adenosine receptor.
abstract: Stimulation of A2A adenosine receptors (AR) promotes anti-inflammatory responses in animal models of allergic rhinitis, asthma, chronic obstructive pulmonary disease, and rheumatic diseases. Herein we describe the results of a research program aimed at identifying potent and selective agonists of the A2AAR as potential anti-inflammatory agents. The recent crystallographic analysis of A2AAR agonists and antagonists in complex with the receptor provided key information on the structural determinants leading to receptor activation or blocking. In light of this, we designed a new series of 2-((4-aryl(alkyl)piperazin-1-yl)alkylamino)-5'-N-ethylcarboxamidoadenosines with high A2AAR affinity, activation potency and selectivity obtained by merging distinctive structural elements of known agonists and antagonists of the investigated target. Docking-based SAR optimization allowed us to identify compound 42 as one of the most potent and selective A2A agonist discovered so far (Ki hA2AAR = 4.8 nM, EC50 hA2AAR = 4.9 nM, Ki hA1AR > 10 000 nM, Ki hA3AR = 1487 nM, EC50 hA2BAR > 10 000 nM).
authors.affiliation: †Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.affiliation: †Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: †Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Saponaro
authors.affiliation: †Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: †Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.affiliation: †Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.affiliation: §DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: ∥Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.affiliation: ∥Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: ‡Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: ‡Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 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, 44121 Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: ‡Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000737:chemistry; D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D062105:Molecular Docking Simulation; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058908:Adenosine A2 Receptor Agonists; D043705:Receptor, Adenosine A2A; D019830:Adenosine-5'-(N-ethylcarboxamide)