title: Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A1 adenosine receptor. A position-dependent effect study.
abstract: The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electron-withdrawing groups on the phenyl ring at the 4- and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Carlota
authors.initials: C
authors.lastname: Lopez-Cara
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.affiliation: King Pharmaceuticals Inc., Research and Development, 4000 CentreGreen Way, Suite 300, Cary, NC 27513, USA.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, P. O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Arnault
authors.initials: A
authors.lastname: Massink
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, P. O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D013876:Thiophenes
keywords: A(1) adenosine receptor; Allosteric modulator; Anti-nociceptive effect; G protein-coupled receptors