title: Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.
abstract: This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: mfobnisk@cyf-kr.edu.pl.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków 30-688, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rybka
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Góra
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków 30-688, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Żmudzki
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000008:administration & dosage; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: C000612711:3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid; C000612712:3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid; D000577:Amides; D000927:Anticonvulsants; D011759:Pyrrolidines; D010433:Pentylenetetrazole
keywords: Anesthetic activity; Anticonvulsant activity; Antinociceptive properties; Ion channels; Succinimides