Identifying the metabolites of a drug has become an indispensable task in the development of new drugs. Dipfluzine (Dip) is a promising candidate for the treatment of cerebral vascular diseases and has 5 metabolites (M1∼M5) in rat urine and liver microsomes, but their biological activity is still unknown. Because selective cerebral vasodilation is a main role of Dip, we investigated the vasodilation of Dip and its 5 metabolites in isolated Sprague-Dawley (SD) male rat basilar arteries preconstricted with high-K⁺ or 5-HT. The results showed that only M1 possessed concentration-dependent inhibitory activity on the vasoconstriction of arteries with or without the endothelium, and M1 has a more potent vasodilatory effect than Dip on both contraction models. Like Dip, the vasodilatory mechanisms of M1 may be not only related to receptor-operated and voltage-dependent calcium ion channels of smooth muscle cells but also to the release of NO and EDHF from endothelial cells and the opening of Ca²⁺-activated K⁺ channels and ATP-sensitive potassium ion channels. Unlike Dip, the vasodilation mechanism of M1 is also related to the opening of voltage-sensitive K⁺ channel. Together with more selectivity to non-VDCC than Dip, this may partially explain why M1 has stronger vasodilatory effects than Dip. The mechanisms of vasodilation of Dip and M1 may result from the combined action of these or other factors, especially blocking non-endothelium dependent non-VDCC and endothelium dependent IK_Ca channels. These results point to the possibility that M1 provides synergism for the clinical use of Dip, which may inform the synthesis of new drugs.

鉴定药物的代谢产物已成为新药开发中必不可少的任务。Dipfluzine（Dip）是治疗脑血管疾病的有前途的候选药物，在大鼠尿液和肝微粒体中有5种代谢物（M1〜M5），但其生物学活性仍然未知。由于选择性脑血管舒张作用是Dip的主要作用，因此我们研究了Dip及其5种代谢物在高K ⁺预收缩的离体Sprague-Dawley（SD）雄性大鼠基底动脉中的舒张作用。或5-HT。结果表明，只有M1对有或没有内皮的动脉血管收缩具有浓度依赖性抑制活性，并且在两种收缩模型上，M1均比Dip具有更强的血管舒张作用。与Dip一样，M1的血管舒张机制不仅可能与平滑肌细胞的受体操纵性和电压依赖性钙离子通道有关，而且可能与内皮细胞中NO和EDHF的释放以及Ca ²⁺活化的K的开放有关⁺通道和ATP敏感的钾离子通道。与Dip不同，M1的血管舒张机制还与电压敏感K ⁺的打开有关。渠道。再加上对非VDCC的选择性比Dip高，这可以部分解释为什么M1具有比Dip更强的血管舒张作用。Dip和M1的血管舒张机制可能是由这些因素或其他因素的共同作用引起的，尤其是阻断非内皮依赖性的非VDCC和内皮依赖性的IK _Ca通道。这些结果表明，M1可为Dip的临床应用提供协同作用，这可能有助于合成新药。