title: Synthesis and biological evaluation of novel allosteric enhancers of the A1 adenosine receptor based on 2-amino-3-(4'-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene.
abstract: A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, whereas reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [(3)H]NECA, from the receptor.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara , Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: Arnault
authors.initials: A
authors.lastname: Massink
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Luisa Carlota
authors.initials: LC
authors.lastname: Lopez-Cara
authors.forename: Giulia
authors.initials: G
authors.lastname: Saponaro
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
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; D000818:Animals; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007700:Kinetics; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D013876:Thiophenes