Investigation into stereoselective pharmacological activity of phenotropil

Basic Clin Pharmacol Toxicol. 2011 Nov;109(5):407-12. doi: 10.1111/j.1742-7843.2011.00742.x. Epub 2011 Jul 20.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Central Nervous System / drug effects
  • Chromatography, Liquid / methods
  • Male
  • Memory / drug effects*
  • Mice
  • Mice, Inbred CBA
  • Mice, Inbred ICR
  • Motor Activity / drug effects*
  • Piracetam / analogs & derivatives*
  • Piracetam / pharmacology
  • Stereoisomerism
  • Swimming
  • Tandem Mass Spectrometry / methods


  • Antidepressive Agents
  • 4-phenylpiracetam
  • Piracetam