Article

European Journal of Drug Metabolism and Pharmacokinetics

, Volume 22, Issue 3, pp 245-252

First online:

The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-l-prolylglycine

  • T. A. GudashevaAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
  • , S. S. BoykoAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
  • , R. U. OstrovskayaAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
  • , T. A. VoroninaAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
  • , V. K. AkparovAffiliated withState Institute of Genetic and Selection of Industrial Microorganisms
  • , S. S. Trofimov
  • , G. G. RozantsevAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
  • , A. P. SkoldinovAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
  • , V. P. ZherdevAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science
    • , S. B. SeredeninAffiliated withChemistry Department, Institute of Pharmacology, Russian Academy of Medical Science

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Summary

The metabolism of a new piracetam analogue, the dipeptide cognitive enhancer N-phenylacetyl-l-prolylglycine ethyl ester (GVS-111) was studied in vivo. GVS-111 itself was not found in rat brain 1 h after 5 mg/kg i.p. administration up to limit of detection (LOD) under high performance liquid chromatography (HPLC) conditions. Three substances corresponding to the three possible GVS-111 metabolites, namely phenylacetic acid, prolylglycine and cyclo-prolylglycine, were found in experimental rat brain samples as well as in controls using HPLC, gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) methods. Only cyclo-prolylglycine concentration increased (2.5-fold) 1 h after GVS-111 administration. Cyclo-prolylglycine formation from GVS-111 in the presence of plasma and brain enzymes was shown in vitro. These data could be considered as evidence that GVS-111 is prodrug which converts in the body to cyclo-prolylglycine, and which is identical to the endogenous cyclopeptide that produces the nootropic activity.

Keywords

Cognitive enhancer piracetam analogue N-phenylacetylprolylglycine ethyl ester metabolism cyclo-prolylglycine gas chromatography-mass spectrometry