Synthesis and Biological Evaluation of Novel Allosteric Enhancers of the A 1 Adenosine Receptor Based on 2-Amino-3-(4′-Chlorobenzoyl)-4-Substituted-5-Arylethynyl Thiophene

✍ Scribed by Romagnoli, Romeo; Baraldi, Pier Giovanni; IJzerman, Adriaan P.; Massink, Arnault; Cruz-Lopez, Olga; Lopez-Cara, Luisa Carlota; Saponaro, Giulia; Preti, Delia; Aghazadeh Tabrizi, Mojgan; Baraldi, Stefania; Moorman, Allan R.; Vincenzi, Fabrizio; Borea, Pier Andrea; Varani, Katia

• Book ID: 126296976
• Publisher: American Chemical Society
• Year: 2014
• Tongue: English
• Weight: 772 KB
• Volume: 57
• Category: Article
• ISSN: 0022-2623
• DOI: 10.1021/jm5008853

✦ Synopsis

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.