title: PRELIMINARY EVALUATION OF CENTRAL NERVOUS SYSTEM ACTIVITY OF (E)-N-2-METHYL-3-PHENYLPROP-2-ENYL ((E)-N- α-METHYLCINNAMYL) DERIVATIVES OF SELECTED AMINOALKANOLS.
abstract: A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2-aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gunia-Krzyzak
authors.forename: Karolina
authors.initials: K
authors.lastname: Pytka
authors.forename: Karolina
authors.initials: K
authors.lastname: Słoczyńska
authors.forename: Anna M
authors.initials: AM
authors.lastname: Waszkielewicz
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Marek
authors.initials: M
authors.lastname: Cegła
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pekala
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001711:Biotransformation; D002934:Cinnamates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004597:Electroshock; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008744:Methylamines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D010433:Pentylenetetrazole; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D000928:Antidepressive Agents; D002934:Cinnamates; D008744:Methylamines; D010433:Pentylenetetrazole