title: Design, synthesis, anticonvulsant, and antiarrhythmic properties of novel N-Mannich base and amide derivatives of β-tetralinohydantoin.
abstract: BACKGROUND
  5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, two small series of amine derivatives (Mannich bases) and amide ones were designed containing β-tetralinohydantoin system. In preliminary studies, some of arylpiperazinylmethyl derivatives with a β-tetralinohydantoin moiety were effective in screening anticonvulsant tests in mice.
  
  
  METHODS
  These new amine and amide derivatives of β-tetralinohydantoin were evaluated in standard anticonvulsant screens (maximal electroshock (MES) or pentylenetetrazole (scPTZ) seizure tests) and their neurotoxicity was assessed in standardized rotarod tests. Additionally, due to structural features (a hydantoin ring), influence on antiarrhythmic activity, electrocardiogram components and blood pressure was tested in rats.
  
  
  RESULTS
  The new N-Mannich bases were effective in maximal electroshock or pentylenetetrazole seizures screens; and the most interesting compound 4 (1-{[4-(1-phenyethyl)-piperazin-1-yl]methyl}-3',4'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,2'-naphthalene]-2,5-dione) displayed anticonvulsant activity in both the aforementioned tests. Furthermore, compound 6, an amide derivative of β-tetralinohydantoin, displayed significant antiarrhythmic activity in a barium chloride-induced arrhythmia model (ED50 16.3mg/kg), but it was devoid of anticonvulsant protection. None of the tested compounds affected the electrocardiogram components or blood pressure in normotensive rats.
  
  
  CONCLUSIONS
  All new N-Mannich bases containing the β-tetralinohydantoin system and 1-phenylalkylpiperazine were classified to Anticonvulsant Screening Program 1st class. In contrast, our results suggested that the introduction of an amide bond in the alkyl side chain of the β-tetralinohydantoin system abolished the anticonvulsant activity, but not the antiarrhythmic one. However, further studies are required for a definitive conclusion.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland. Electronic address: aczopek@cm-uj.krakow.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Czopek
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Byrtus
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagórska
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D000927:Anticonvulsants / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D004597:Electroshock / Q000379:methods; D008297:Male; D008352:Mannich Bases / Q000737:chemistry*; D020258:Neurotoxicity Syndromes / Q000209:etiology; D010433:Pentylenetetrazole / Q000737:chemistry; D010672:Phenytoin / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test / Q000379:methods; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D008352:Mannich Bases; D010672:Phenytoin; D010433:Pentylenetetrazole
keywords: Antiarrhythmics; Anticonvulsants; Hydantoin; Imidazolidine-2,4-dione