Design of N-acylprolyltyrosine "tripeptoid" analogues of neurotensin as potential atypical antipsychotic agents.

A series of N-acylprolyltyrosine amides was designed as tripeptoid analogues of neurotensin. The substituted dipeptides were tested in vivo for antidopamine activity by their ability to inhibit the apomorphine-induced climbing in mice and the dopamine-induced extrapolatory behavior impairment in rats. The N-acylprolyltyrosine amides structure-activity relationships have indicated the size of the N-acyl group and the configuration of amino acids that are important for the activity. We found that the bioactivity has been increased dramatically when the n-hydrocarbon chain on the N-acyl group was increased from four to five carbon atoms. The activity seems to reside exclusively in the L-Tyr diastereomers. All of the compounds tested were inactive in the cataleptogenic action and did not exhibit the acute toxicity even at doses 500-1000 times higher than ED50 in climbing test. On this basis, the N-acylprolyltyrosine amides could potentially be a novel class of atypical antipsychotic agents.

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.

[The pharmacokinetics of the dipeptide analog of piracetam with nootropic activity GVS-111 and of its basic metabolites]. / Farmakokinetika dipeptidnogo analoga piratsetama s nootropnoi aktivnost'iu GVS-111 i ego osnovnykh metabolitov.

The pharmacokinetics of a new nootropic dipeptide analog of piracetam-N-phenylacetyl-L-prolylglycine (GWS-111) and its main metabolites were studied in rats by means of high performance liquid chromatography and gas-liquid chromatography. The compound under study showed a greater resistance to an enzymatic effect than natural neuropeptides. In addition to an unchanged compound three of its metabolites were found in the blood plasma of the rats. One of them, cyclo-Pro-Gly was an active metabolite of GWS-111.

Identification of a novel endogenous memory facilitating cyclic dipeptide cyclo-prolylglycine in rat brain.

Using high-performance liquid chromatography, gas-chromatography and chromato-mass spectrometry methods a novel endogenous cyclic dipeptide cyclo-prolylglycine was identified in rat brain. Its content according to gas chromatography is 2.8 +/- 0.3 nmol/g wet brain. Synthetic cyclo-prolylglycine has demonstrated antiamnesic activity in the passive avoidance test in rats at a dose of 0.1 mg/kg i.p. Cyclic dipeptide cyclo-prolylglycine seems to be a memory facilitating substance and its presence in rat brain suggests the existence of a new mechanism of memory regulation.

[The use of the HPLC method for the quantitative determination of a peptide analog of piracetam with nootropic activity and its main metabolites]. / Primenenie metoda VEZhK dlia kolichestvennogo opredeleniia peptidnogo analoga piratsetama s nootropnoi aktivnost'iu i ego osnovnykh metabolitov.

HPLC method has been developed for pharmacokinetic study of nootropic peptide analog of pyracetam GVS-111 and its main metabolites. In the model experiments on rats the enzymes of blood plasma were shown to metabolize GVS-111 during 1-h incubation with the formation of metabolite, phenylacetylproline. This suggests that in vivo experiments these blood plasma enzymes will also be actively involved in the metabolism of the compound tested. The liver tissue enzymes metabolized GVS-111 much slower.