title: In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents.
abstract: Epilepsy is a common neurological disorder caused by an imbalance between inhibitory and excitatory neurotransmission. It is well known that neuronal excitability is related to γ-aminobutyric acid (GABA)ergic depolarization. HCO3 (-) -dependent depolarization can be suppressed by membrane-permeable inhibitors of carbonic anhydrase. We previously identified some isoquinoline sulfonamides as potent and selective inhibitors of the human carbonic anhydrase II and VII (hCA II and hCA VII) isoforms. Given that hCA II and hCA VII are specific isoforms involved in GABA-mediated neuronal excitation, we hypothesized that they could represent the biological target for the development of new anticonvulsant agents. Therefore, for selected isoquinoline sulfonamides, we preliminarily tested their ability to prevent audiogenic seizures in DBA/2 mice. All compounds were evaluated after intraperitoneal administration, and some of them proved to protect the mice against convulsions. Among this series of compounds, several derivatives showed combined in vivo efficacy with inhibitory effects toward the targeted carbonic anhydrases (i.e., hCA II and hCA VII). Specifically, the most interesting molecule was 1-(4-aminophenyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamide (6), which proved to be a more active and selective hCA VII inhibitor than the reference compound topiramate. Further studies to explore the in vivo pharmacokinetic profile of the most active compounds may help to provide insight into the future design of selective hCA VII inhibitors.
authors.affiliation: Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale Annunziata, 98168, Messina, Italy. brunoe@unime.it.
authors.forename: Elvira
authors.identifier: 0000-0001-5192-448X
authors.initials: E
authors.lastname: Bruno
authors.affiliation: Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale Annunziata, 98168, Messina, Italy.
authors.forename: Maria R
authors.identifier: 0000-0003-3704-0076
authors.initials: MR
authors.lastname: Buemi
authors.affiliation: Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale Annunziata, 98168, Messina, Italy.
authors.forename: Laura
authors.identifier: 0000-0003-0614-5713
authors.initials: L
authors.lastname: De Luca
authors.affiliation: Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale Annunziata, 98168, Messina, Italy.
authors.forename: Stefania
authors.identifier: 0000-0003-0841-9626
authors.initials: S
authors.lastname: Ferro
authors.affiliation: Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale Annunziata, 98168, Messina, Italy.
authors.forename: Anna-Maria
authors.identifier: 0000-0002-3149-9639
authors.initials: AM
authors.lastname: Monforte
authors.affiliation: Neurofarba: Department of Neuroscience, Psychology, Pharmaceuticals and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.identifier: 0000-0003-4262-0323
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Neurofarba: Department of Neuroscience, Psychology, Pharmaceuticals and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Daniela
authors.identifier: 0000-0002-1352-1900
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Viale Europa Località Germaneto, 88100, Catanzaro, Italy.
authors.forename: Giovambattista
authors.identifier: 0000-0002-7629-6579
authors.initials: G
authors.lastname: De Sarro
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Viale Europa Località Germaneto, 88100, Catanzaro, Italy.
authors.forename: Emilio
authors.identifier: 0000-0002-1279-8123
authors.initials: E
authors.lastname: Russo
authors.affiliation: Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale Annunziata, 98168, Messina, Italy. rgitto@unime.it.
authors.forename: Rosaria
authors.identifier: 0000-0003-0002-2253
authors.initials: R
authors.lastname: Gitto
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases
keywords: anticonvulsants; carbonic anhydrases; inhibitors; isoquinoline sulfonamides; sulfur