title: Structure-activity relationships of 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophenes. Part 2: Probing the influence of diverse substituents at the phenyl of the arylpiperazine moiety on allosteric enhancer activity at the A₁ adenosine receptor.
abstract: In a preliminary article, we reported the potent allosteric enhancer activity at the A(1) adenosine receptor of a small series of 2-amino-3-(4-chlorobenzoyl)-4-[4-(aryl)piperazin-1-yl)methyl]thiophene derivatives bearing electron-withdrawing or electron-releasing groups at the para-position of the phenylpiperazine moiety. In the present study, we report the development of the compounds previously studied by modifying both the number and position of substituents on the phenylpiperazine moiety, aimed at establishing a structure-activity relationship identifying additional compounds with improved activity. The nature and the position of substituents on the phenyl ring tethered to the piperazine seemed to exert a fundamental influence on the allosteric enhancer activity, with the 3,4-difluoro 4i, 3-chloro-4-fluoro 4o, and 4-trifluoromethoxy 4ak derivatives being the most active compounds in binding (saturation and competition experiments) and functional cAMP studies. This study shows that it is also possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A(1) adenosine receptor.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. rmr@unife.it
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Maria Dora
authors.initials: MD
authors.lastname: Carrion
authors.forename: Carlota Lopez
authors.initials: CL
authors.lastname: Cara
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Maria Kimatrai
authors.initials: MK
authors.lastname: Salvador
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D010879:Piperazines; D043682:Receptor, Adenosine A1; D013876:Thiophenes; D000242:Cyclic AMP