Spirocyclic Benzopyran-Based Derivatives as New Anti-ischemic Activators of Mitochondrial ATP-Sensitive Potassium Channel

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• 作者：Maria C. Breschi ; Vincenzo Calderone ; Maria Digiacomo ; Mariaelisa Manganaro ; Alma Martelli ; Filippo Minutolo ; Simona Rapposelli ; Lara Testai ; Federica Tonelli ; Aldo Balsamo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：November 13, 2008
• 年：2008
• 卷：51
• 期：21
• 页码：6945-6954
• 全文大小：203K
• 年卷期：v.51,no.21(November 13, 2008)
• ISSN：1520-4804

文摘

Heart mitochondrial ATP-sensitive potassium channels (mito-K_ATP channels) are deeply implicated in the self-defense mechanism of ischemic preconditioning. Therefore, exogenous molecules activating these channels are considered as a promising pharmacological tool to reduce the myocardial injury deriving from ischemia/reperfusion events. This paper reports the synthesis and pharmacological evaluation of original spiromorpholine- and spiromorpholone-benzopyran derivatives, with the aim to obtain selective activators of mito-K_ATP channels. Some compounds of this series showed appreciable cardioprotective effects on rat isolated and perfused hearts, submitted to ischemia/reperfusion cycles. The selective mito-K_ATP channel blocker 5-hydroxydecanoic acid antagonized the anti-ischemic activity, indicating a clear implication of this pharmacological target. Furthermore, these effects were not associated with significant hypotensive and vasorelaxing properties, which represent one of the main limiting factors for the clinical use of nonselective K_ATP-openers against myocardial ischemia.