Which Carbonic Anhydrases are Targeted by the Antiepileptic Sulfonamides and Sulfamates?
Which Carbonic Anhydrases are Targeted by the Antiepileptic Sulfonamides and Sulfamates?
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DOI：
10.1111/j.1747-0285.2009.00857.x
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发表时间：
2009-09-01
影响因子：
3
通讯作者：
Supuran, Claudiu T.
中科院分区：
文献类型：
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作者：
De Simone, Giuseppina;Scozzafava, Andrea;Supuran, Claudiu T.
临床上使用的抗癫痫药唑尼沙胺、舒硫胺和托吡酯是哺乳动物碳酸酐酶异构体 I-XIV 的抑制剂，以不同的功效无差别地抑制哺乳动物中存在的所有催化活性异构体。然而，尚不清楚哪种碳酸酐酶同工酶可能负责此类磺酰胺/氨基磺酸盐药物的抗惊厥活性。我们在这里检查了上述抗癫痫药物以及两种研究中的、结构相关的磺胺类药物对所有哺乳动物碳酸酐酶的完全抑制作用，其中一种是抗惊厥药，另一种不是抗惊厥药。没有明确的数据使我们能够提出参与这些过程的碳酸酐酶，但强碳酸酐酶 II、VII、IX 和 XII 抑制作用，与足够高的脂溶性相关，可能会导致此类药理学类别的有效抗惊厥药。因此，有必要进行进一步的研究以更好地理解这些现象。哺乳动物大脑中存在的此类碳酸酐酶的抑制是否可能与设计用于治疗神经系统疾病的药物制剂或了解其中一些药物的多因素作用机制相关，这是一个肯定值得进一步研究的主题。
Zonisamide, sulthiame, and topiramate, clinically used antiepileptics are inhibitors of mammalian carbonic anhydrase isoforms I-XIV, indiscriminately inhibiting with variable efficacy all the catalytically active isoforms present in mammals. However, it is not clear which carbonic anhydrase isozymes might be responsible for the anticonvulsant activity of such sulfonamide/sulfamate drugs. We examine here the full inhibition profile against all mammalian carbonic anhydrases of the above antiepileptic drugs together with two investigational, structurally related sulfonamides, one of which is and the other is not an anticonvulsant. No clear-cut data allow us to propose which are the carbonic anhydrases involved in these processes, but strong carbonic anhydrase II, VII, IX, and XII inhibition, correlated with sufficiently high liposolubility may lead to effective anticonvulsants of this pharmacological class. Therefore, further studies are warranted for better understanding these phenomena. Whether the inhibition of such carbonic anhydrases present in the mammalian brain might be relevant for designing pharmacological agents useful in the management of neurological disorders or for understanding the multifactorial mechanism of action of some of these drugs is a topic which surely deserves further investigations.