title: Synthesis and biological effects of novel 2-amino-3-(4-chlorobenzoyl)-4-substituted thiophenes as allosteric enhancers of the A1 adenosine receptor.
abstract: Allosteric enhancers for the A1 adenosine receptor represent a novel and unique drug design strategy to augment the response to endogenous adenosine in a site- and event-specific manner. We have previously investigated a detailed structure-activity relationship study around a wide series of 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A1 adenosine receptor. In this manuscript we report our investigation on the influence on allosteric enhancer activity of further substitution at the 4-position of the 2-amino-3-(4-chlorobenzoyl)-thiophene system to explore bulk tolerance by replacement of the arylpiperazine moiety with a series of fused indole nuclei corresponding to 1,2,3,4-tetrahydropyrazino[1,2-a]indole, 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, tetrahydro-γ-carboline, tetrahydroisoquinoline, spiro-1,3-benzodioxolepiperidine, aliphatic tertiary amine, N-alkylaniline, aryl ether and aryl thioether templates. The 1,2,3,4-tetrahydropyrazino[1,2-a]indole derivatives 3a-c and 3e 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. This study also shows that it is possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A1 adenosine receptor.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. Electronic address: 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
authors.initials: C
authors.lastname: Lopez Cara
authors.forename: Maria
authors.initials: M
authors.lastname: Kimatrai Salvador
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
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: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; 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: D043682:Receptor, Adenosine A1; D013876:Thiophenes
keywords: 2-Amino-3-benzoylthiophene; A(1) adenosine receptor; Allosteric enhancer; G protein-coupled receptors