title: Investigation into stereoselective pharmacological activity of phenotropil.
abstract: Phenotropil [N-carbamoylmethyl-4-aryl-2-pyrrolidone (2-(2-oxo-4-phenyl-pyrrolidin-1-yl) acetamide; carphedon)] is clinically used in its racemic form as a nootropic drug that improves physical condition and cognition. The aim of this study was to compare the stereoselective pharmacological activity of R- and S-enantiomers of phenotropil in different behavioural tests. Racemic phenotropil and its enantiomers were tested for locomotor, antidepressant and memory-improving activity and influence on the central nervous system (CNS) using general pharmacological tests in mice. After a single administration, the amount of compound in brain tissue extracts was determined using an ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method in a positive ion electrospray mode. In the open-field test, a significant increase in locomotor activity was observed after a single administration of R-phenotropil at doses of 10 and 50 mg/kg and S-phenotropil at a dose of 50 mg/kg. In the forced swim test, R-phenotropil induced an antidepressant effect at doses of 100 and 50 mg/kg, and S-phenotropil was active at a dose of 100 mg/kg. R-phenotropil significantly enhanced memory function in a passive avoidance response test at a dose of 1 mg/kg; the S-enantiomer did not show any activity in this test. However, the concentrations of R- and S-phenotropils in brain tissue were similar. In conclusion, the antidepressant and increased locomotor activity relies on both R- and S-phenotropils, but the memory-improving activity is only characteristic of R-phenotropil. These results may be important for the clinical use of optically pure isomers of phenotropil.
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia. liga@biomed.lu.lv
authors.forename: Liga
authors.initials: L
authors.lastname: Zvejniece
authors.forename: Baiba
authors.initials: B
authors.lastname: Svalbe
authors.forename: Grigory
authors.initials: G
authors.lastname: Veinberg
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.forename: Maksims
authors.initials: M
authors.lastname: Vorona
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D013237:Stereoisomerism; D013550:Swimming; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000928:Antidepressive Agents; C037917:4-phenylpiracetam; D010889:Piracetam