The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine.
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.
Gudasheva
T A
TA
Institute of Pharmacology, Russian Academy of Medical Science, Moscow, Russia.
Boyko
S S
SS
Ostrovskaya
R U
RU
Voronina
T A
TA
Akparov
V K
VK
Trofimov
S S
SS
Rozantsev
G G
GG
Skoldinov
A P
AP
Zherdev
V P
VP
Seredenin
S B
SB
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism*; D010889:Piracetam / Q000494:pharmacology; D051381:Rats
D004151:Dipeptides; D009479:Neuropeptides; D018697:Nootropic Agents; C057749:prolylglycine; C103871:ethyl phenylacetyl-Pro-Gly; D010889:Piracetam