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In view of the intractability of neonatal seizures, the preclinical findings prompted a clinical trial in neonates on bumetanide as an add\u2010on to phenobarbital, which, however, had to be terminated because of ototoxicity and lack of efficacy. We have recently shown that bumetanide penetrates only poorly into the brain, so that we developed lipophilic prodrugs such as <jats:styled-content style=\"fixed-case\">BUM<\/jats:styled-content>5, the N,N\u2010dimethylaminoethylester of bumetanide, which penetrate more easily into the brain and are converted to bumetanide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the present study, we used a new strategy to test whether <jats:styled-content style=\"fixed-case\">BUM<\/jats:styled-content>5 is more potent than bumetanide in potentiating the antiseizure effect of phenobarbital. Adult mice were made epileptic by pilocarpine, and the antiseizure effects of bumetanide, <jats:styled-content style=\"fixed-case\">BUM<\/jats:styled-content>5, and phenobarbital alone or in combination were determined by the maximal electroshock seizure threshold test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In nonepileptic mice, only phenobarbital exerted seizure threshold\u2013increasing activity, and this was not potentiated by the <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 inhibitors. In contrast, a marked potentiation of phenobarbital by <jats:styled-content style=\"fixed-case\">BUM<\/jats:styled-content>5, but not bumetanide, was determined in epileptic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Thus, bumetanide is not capable of potentiating phenobarbital's antiseizure effect in an adult mouse model, which, however, can be overcome by using the prodrug <jats:styled-content style=\"fixed-case\">BUM<\/jats:styled-content>5. These data substantiate that <jats:styled-content style=\"fixed-case\">BUM<\/jats:styled-content>5 is a promising tool compound for target validation and proof\u2010of\u2010concept studies on the role of <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 in brain diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13346","type":"journal-article","created":{"date-parts":[[2016,2,27]],"date-time":"2016-02-27T14:10:06Z","timestamp":1456582206000},"page":"698-705","source":"Crossref","is-referenced-by-count":48,"title":["The bumetanide prodrug <scp>BUM<\/scp>5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice"],"prefix":"10.1111","volume":"57","author":[{"given":"Thomas","family":"Erker","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry University of Vienna Vienna 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