Synthesis and α₁-adrenoceptor antagonist activity of derivatives and isosters of the furan portion of (+)-cyclazosin

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• 作者：Gianni Sagratini ; Piero Angeli ; Michela Buccioni ; Ugo Gulini ; Gabriella Marucci ; Carlo Melchiorre ; Amedeo Leonardi ; Elena Poggesi ; Dario Giardinà
• 关键词：α ; ₁-Adrenoceptor subtypes ; α ; ₁-Adrenoceptor antagonists ; α ; _1B-Adrenoceptor selective antagonists ; (+)-Cyclazosin analogues
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 March 2007
• 卷：15
• 期：6
• 页码：2334-2345
• 文件大小：312 K

摘要

α₁-Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of α₁-adrenoceptor subtypes. We synthesized and studied the α₁-adrenoceptor blocking properties of new molecules structurally related to the α_1B-adrenoceptor selective antagonist (+)-cyclazosin, in an attempt to improve its receptor selectivity. In particular, we investigated the importance of substituents introduced at position 5 of the 2-furan moiety of (+)-cyclazosin and its replacement with classical isosteric rings. The 5-methylfuryl derivative (+)-3, [(+)-metcyclazosin], improved the pharmacological properties of the progenitor, displaying a competitive antagonism and an 11 fold increased selectivity for α_1B over α_1A, while maintaining a similar selectivity for the α_1B-adrenoceptor relative to the α_1D-adrenoceptor. Compound (+)-3 may represent a useful tool for α_1B-adrenoceptor characterization in functional studies.