title: Design, synthesis and biological activity of new amides derived from 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid.
abstract: A series of new 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides (6-23) has been synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotarod test. The in vivo preliminary pharmacological results showed that in the whole series only two compounds (15, 21) were devoid of activity, whereas other molecules revealed protection in at least one animal model of epilepsy (MES or/and scPTZ). The in vivo quantitative studies in mice showed that in the MES test the most active were 1-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (17), 1-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8), and its 2-fluorophenyl analog (7) with ED50 values of 97.51 mg/kg (17), 104.11 mg/kg (8), and 114.68 mg/kg (7), respectively. In the scPTZ screen the most potent were compound 6 with an ED50 = 40.87 mg/kg, and 4-benzylpiperidine derivative 22 - ED50 = 60.00 mg/kg. Furthermore, selected compounds 8, 14, 17, and 23 were tested in the psychomotor seizure 6-Hz test. Compounds 7, 8, and 17 revealed significant analgesic activity in the formalin model of tonic pain in mice, without impairment of the motor coordination in the chimney test. The in vitro binding studies showed that the mechanism of anticonvulsant activity may be partially related with the influence on the voltage-gated sodium and calcium channels. The mutagenic and antimutagenic effects of 13, 17, and 22 were evaluated using the novel Vibrio harveyi assay.
authors.affiliation: Department of Medicinal Chemistry, 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, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rybka
authors.affiliation: Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Powroźnik
authors.affiliation: Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Żmudzki
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / 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; D015195:Drug Design; D004597:Electroshock; D007274:Injections, Intraperitoneal; D051379:Mice; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy*
chemical_list: C000608142:3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid; D000085:Acetates; D000577:Amides; D000927:Anticonvulsants; D011759:Pyrrolidines
keywords: Anticonvulsant activity; Antinociceptive properties; In vivo and in vitro studies; Mutagenicity and antimutagenicity studies; Succinimides