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

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 2; pp. 996 - 1007
• Main Authors: Romagnoli, Romeo, Baraldi, Pier Giovanni, Carrion, Maria Dora, Cara, Carlota Lopez, Cruz-Lopez, Olga, Salvador, Maria Kimatrai, Preti, Delia, Tabrizi, Mojgan Aghazadeh, Shryock, John C., Moorman, Allan R., Vincenzi, Fabrizio, Varani, Katia, Borea, Pier Andrea
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.01.2012
• Subjects: 2-Amino-3-benzoylthiophene; A1 adenosine receptor; adenosine; Adenosine A1 Receptor Antagonists - chemical synthesis; Adenosine A1 Receptor Antagonists - chemistry; Adenosine A1 Receptor Antagonists - pharmacology; Allosteric enhancer; Allosteric Regulation; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP - metabolism; G protein-coupled receptors; Humans; piperazine; Piperazines - chemistry; Protein Binding - drug effects; Receptor, Adenosine A1 - chemistry; Receptor, Adenosine A1 - metabolism; Structure-Activity Relationship; structure-activity relationships; thiophene; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Allosteric enhancer; 2-Amino-3-benzoylthiophene; G protein-coupled receptors; A1 adenosine receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.11.044

In a preliminary article, we reported the potent allosteric enhancer activity at the A1 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 A1 adenosine receptor.