title: New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones.
abstract: The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address: k.kaminski@uj.edu.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland.
authors.forename: Mirosław
authors.initials: M
authors.lastname: Zagaja
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland; Department of Pathophysiology, Medical University of Lublin, Ceramiczna 1, 20-150 Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Łuszczki
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Andres-Mach
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Abram
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007274:Injections, Intraperitoneal; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010433:Pentylenetetrazole / Q000008:administration & dosage; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: C000611506:3,3-dimethyl-1-(1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl)pyrrolidine-2,5-dione; C000611510:3-methyl-1-(1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl)pyrrolidine-2,5-dione; D000700:Analgesics; D000927:Anticonvulsants; D010879:Piperazines; D011760:Pyrrolidinones; D010433:Pentylenetetrazole
keywords: Anticonvulsant activity; Hybrid compounds; In vivo studies; MES test; Pyrrolidine-2,5-dione; Six-Hertz (6Hz) test; Succinimide; scPTZ test