title: Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one.
abstract: BACKGROUND
  The aim of this study was to synthesize a series of new N-Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties.
  
  
  METHODS
  The target compounds 8-12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one (7) by a Mannich-type reaction. The obtained compounds were assessed and tested for their anticonvulsant activity in two screening mouse models of seizures, i.e., the maximal electroshock (MES) test and in the subcutaneous pentylenetetrazole (scPTZ) test. The effect of these compounds on animals' motor coordination was measured in the rotarod test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals' locomotor activity was also evaluated.
  
  
  RESULTS
  Compound 8 showed protection (25%) in the MES and in the scPTZ tests at the dose of 100mg/kg and was not neurotoxic. In the four-plate test, compound 8 at the dose of 30mg/kg showed a statistically significant (p<0.05) anxiolytic-like activity. In the forced swim test, it reduced the immobility time by 24.3% (significant at p<0.05), which indicates its potential antidepressant-like properties. In the locomotor activity test, compound 8 significantly reduced animals' locomotor activity by 79.9%.
  
  
  CONCLUSIONS
  The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) a promising lead structure for further development.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Malawska
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rak
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Gryzło
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland; Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C St., 15-222 Białystok, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Michałowska
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Żmudzka
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Lodarski
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland. Electronic address: mfmalaws@cyf-kr.edu.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000627:therapeutic use; D000927:Anticonvulsants / Q000737:chemistry* / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000737:chemistry* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D008297:Male; D008352:Mannich Bases / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity; D010879:Piperazines / Q000737:chemistry* / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D000928:Antidepressive Agents; D008352:Mannich Bases; D010879:Piperazines; C031503:phenylpiperazine; D010433:Pentylenetetrazole
keywords: Antidepressant-like activity; Anxiolytic-like activity; MES test; Substituted pyrrolidin-2-one derivatives; scPTZ test