title: Synthesis and biological evaluation of novel 2-amino-3-aroyl-4-neopentyl-5-substituted thiophene derivatives as allosteric enhancers of the A₁ adenosine receptor.
abstract: 2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
authors: Romeo
authors: R
authors: Romagnoli
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: baraldi@unife.it.
authors: Pier Giovanni
authors: PG
authors: Baraldi
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Maria Dora
authors: MD
authors: Carrion
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Olga
authors: O
authors: Cruz-Lopez
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Carlota Lopez
authors: CL
authors: Cara
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Giulia
authors: G
authors: Saponaro
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Delia
authors: D
authors: Preti
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Mojgan Aghazadeh
authors: MA
authors: Tabrizi
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17-19, Università di Ferrara, 44121 Ferrara, Italy.
authors: Stefania
authors: S
authors: Baraldi
authors: King Pharmaceuticals Inc., Research and Development, 4000 Centre Green Way, Suite 300, Cary, NC 27513, United States.
authors: Allan R
authors: AR
authors: Moorman
authors: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.
authors: Fabrizio
authors: F
authors: Vincenzi
authors: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.
authors: Pier Andrea
authors: PA
authors: Borea
authors: Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.
authors: Katia
authors: K
authors: Varani
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D043682:Receptor, Adenosine A1; D013876:Thiophenes
keywords: 2-Amino-3-benzoylthiophene; 2-chloro-N(6)-cyclopentyladenosine; A(1) adenosine receptor; AE(s); Allosteric modulation; CCPA; CHO; CNS; CsF; ERG; EWG; G protein-coupled receptors; GPCRs; N-bromosuccinimide; NBS; PdCl(2)(DPPF); [(3)H](4-(2-[7-amino-2-(2-furil)[1,2.4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol); [(3)H]1,3-dipropyl-8-cyclopentyl-xanthine; [(3)H]2-chloro-N(6)-cyclopentyladenosine; [(3)H]5-N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; [(3)H]CCPA; [(3)H]DPCPX; [(3)H]MRE-3008F20; [(3)H]ZM 241385; [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane; allosteric enhancer(s); cAMP; central nervous system; cesium fluoride; chinese hamster ovary; cyclic adenosine monophosphate; electron-releasing group; electron-withdrawing group; hA(1)AR; human A(1) adenosine receptor