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

Abstract

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.

The relationship between the content of the potential psychopharmacological agent cyclo-L-prolylglycine in the brain of experimental animals and its antihypoxic effect

“…Исследование содержания ЦПГ в целом мозге экспериментальных животных и его региональной и внутриклеточной локализации проводили на белых беспородных крысах-самцах массой 220-250 г и мышах-самцах 2 линий -C57Black/6 и BALB/c массой 18-22 г. Идентификацию и количественное определение ЦПГ в целом мозге и его структурах у беспородных крыс, а также в мозге линейных животных проводили методами ГЖХ-ВЭЖХ-МС/МС [3,4]…”

“…Новый дипептид циклической структуры -цикло-Lпролилглицин (ЦПГ) был впервые обнаружен нами при изучении фармакокинетики ноотропного препарата ноопепт в качестве его активного метаболита [1,2], затем ЦПГ был идентифицирован как эндогенное соединение в мозге крыс, определено его количествен-ное содержание, которое составило 2,8 нм/г влажной массы мозга крыс. Показана методами GC-HPLC-MS-MS идентичность метаболита ноопепта и эндогенного соединения циклической структуры -дипептида ЦПГ [3,4]. При изучении фармакологической активности синтезированного аналога эндогенного ЦПГ показано, что он проявляет ноотропный, нейропротективный и анксиолитический эффекты [5][6][7], для анксиолитической активности была выявлена селективная зависимость эффекта от фенотипа экспериментальных животных и различного содержания ЦПГ в мозге мышей 2-линий -C57Black/6 и BALB/c [8,9].…”

Cyclic‐glycine‐proline accelerates mammary involution by promoting apoptosis and inhibiting IGF‐1 function

“…For instance, cGP is shown to inhibit or promote IGF‐1 function under pathological conditions when IGF‐1 function is relatively increased or diminished, respectively (Guan et al, ). Previous studies have only investigated the roles of cGP in brain development and functional recovery from brain injuries (Guan et al, ; Guan, Zhang, Dale‐Gandar, Hodgkinson, & Vickers, ; Guan et al, ; Gudasheva et al, , Gudasheva et al, ; Singh‐Mallah et al, ), with one study showing the efficacy of cGP in inhibiting IGF‐1‐dependent tumour growth (Guan et al, ). However, the role of cGP in mammary involution, more specifically, in modulating the physiological changes in IGF‐1 function during involution, is not known.…”

Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation

“…This drug-based peptide design led us to the series of acyl-prolyl-containing dipeptides possessing pronounced cognitive enhancing and neuroprotective activities [ 11 ]. Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester, GVS-111, Noopept®) (Figure 1 ) was chosen from this series because of its pronounced nootropic activity [ 12 ], high bioavailability for brain tissues in case of peroral administration [ 13 ] and specificity of its mechanism of action [ 14 ]. Noopept demonstrated wide spectrum of cognition improving effects [ 15 ] as well as pronounced neuroprotective activities both in vivo [ 15 ] and in vitro conditions [ 16 ].…”