Which carbonic anhydrases are targeted by the antiepileptic sulfonamides and sulfamates?

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.