title: Studies on the anticonvulsant activity of 4-alkyl-1,2,4-triazole-3-thiones and their effect on GABAergic system.
abstract: A series of 4-alkyl-5-(3-chlorobenzyl/2,3-dichlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (1a-14a) were designed, synthesized and screened for their anticonvulsant properties. Moreover, the acute adverse-effect profile of the active compounds (1a-7a, 12a) with respect to impairment of motor performance was evaluated in the chimney test. Among 4-alkyl-5-(3-chlorobenzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones, ethyl, butyl, pentyl, hexyl, and heptyl derivatives administered intraperitoneally in a dose of 300 mg/kg protected 100% of the tested animals at four pretreatment times (i.e., 15, 30, 60, 120 min). Taking into account the median effective and toxic doses as well as the time-course profile of anticonvulsant activity, 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (4a) was proposed as the best tolerated and the most promising potential drug candidate. Finally, a radioligand binding assay was used to check whether the anticonvulsant activity of 4-alkyl-1,2,4-triazole-3-thiones was a result of their interactions (direct or allosteric) with GABAA receptor complex and/or their affinity to benzodiazepine (BDZ) binding sites.
authors.affiliation: Department of Organic Chemistry, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland. Electronic address: tomasz.plech@umlub.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Plech
authors.affiliation: Department of Organic Chemistry, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kaproń
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
authors.affiliation: Department of Organic Chemistry, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Paneth
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Żołnierek
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D011963:Receptors, GABA-A; D014230:Triazoles; C013595:mercaptotriazole
keywords: 1,2,4-Triazole-3-thiones; Chimney test; GABAergic system; Maximal electroshock-induced seizure (MES) test; Radioligand binding assay