title: Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A3and A2Asubtypes.
abstract: The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A3or the hA2Areceptor subtype. The N8-(hetero)arylcarboxyamido substituted compounds 4-14 and 21-30, bearing a 6-phenyl moiety or not, respectively, show good hA3receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA2Areceptor subtype (compounds 31-38) and also the 6-phenyl analogues 18-20 do not bind the hA2AAR, or show hA1or balanced hA1/hA2AAR affinity in the micromolar range. Molecular docking of the new hA3antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA3receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA3antagonists herein reported, i.e. the 2,6-diphenyl-8-(3-pyridoylamino)imidazo[1,2-a]pyrazine 29, tested in a rat model of cerebral ischemia, delayed the occurrence of anoxic depolarization caused by oxygen and glucose deprivation in the hippocampus and allowed disrupted synaptic activity to recover.
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Poli
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falsini
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Betti
authors.affiliation: Dipartimento di Scienze Mediche, Sez. Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara, 17-19, 4412 Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.affiliation: Dipartimento di Scienze Mediche, Sez. Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara, 17-19, 4412 Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini, 6, 50139 Firenze, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pugliese
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini, 6, 50139 Firenze, Italy.
authors.forename: Felicita
authors.initials: F
authors.lastname: Pedata
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3-13, 50019, Sesto Fiorentino (FI), Italy; Istituto di Biochimica delle Proteine-CNR, Via P.Castellino 111, 80131 Napoli, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Palchetti
authors.affiliation: Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3-13, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bettazzi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy. Electronic address: daniela.catarzi@unifi.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sez. Farmaceutica e Nutraceutica, Universita' degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D023902:Chromosome Pairing / Q000187:drug effects; D015195:Drug Design; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D043684:Receptor, Adenosine A3 / Q000737:chemistry*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D000588:Amines; D007093:Imidazoles; D058915:Purinergic P1 Receptor Antagonists; D011719:Pyrazines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; C517813:imidazo(1,5-a)pyrazine
keywords: Adenosine receptor antagonists; Bicyclic heteroaromatic systems; G protein-coupled receptors; Imidazopyrazines; Ligand-receptor modeling studies