Synthesis and Biological Evaluation of Novel Allosteric Enhancers of the A1 Adenosine Receptor Based on 2-Amino-3-(4鈥?Chlorobenzoyl)-4-Substituted-5-Arylethynyl Thiophene

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• 作者：Romeo Romagnoli ; Pier Giovanni Baraldi ; Adriaan P. IJzerman ; Arnault Massink ; Olga Cruz-Lopez ; Luisa Carlota Lopez-Cara ; Giulia Saponaro ; Delia Preti ; Mojgan Aghazadeh Tabrizi ; Stefania Baraldi ; Allan R. Moorman ; Fabrizio Vincenzi ; Pier Andrea Borea ; Katia Varani
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 25, 2014
• 年：2014
• 卷：57
• 期：18
• 页码：7673-7686
• 全文大小：548K
• ISSN：1520-4804

文摘

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鈥?b>h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [³H]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, [³H]NECA, from the receptor.