T. A. Voronina

Synthesis and antiamnesic activity of a series of N-acylprolyl-containing dipeptides

Summary Esters and amides of a series of N -acylprolyl-containing dipeptides were synthesized. It was established that these substances possess the ability to prevent memory decline evoked by maximal electroshock (MES) in a passive avoidance step-through paradigm. These N -acylprolyl-containing dipeptides were designed as analogues of pyroglutamyl-containing dipeptides, which we previously demonstrated to be highly active nootropics. Among the structure—activity relationships explored were the effect of N -acyl-substitution size, C-terminal substitution and the nature of the second amino acid. The optimal N -acyl moiety was the N -phenyl-acetyl group, while the optimal C-terminal substitution-esters were those derived from low alkyl alcohols. The optimal second amino acids were Asp, Glu or their fragments, Gly, β-Ala, GABA. Compound 1 ( N -phenylacetylprolylglycine ethyl ester) was selected for further evalution in impaired cognitive functions. It was supposed that esters and unsubstituted amides of N -acylprolylglycines are prodrugs, which convert to the bioactive cyclo-(Pro-Gly) by virtue of enzymatic or chemical lability within the body.

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

SummaryThe 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 effects of piracetam and its novel peptide analogue GVS-111 on neuronal voltage-gated calcium and potassium channels☆

1. With the use of the two-microelectrode voltage-clamp method, three types of voltage-activated ionic currents were examined in isolated neurons of the snail Helix pomatia: high-threshold Ca2+ current (ICa), high-threshold Ca(2+)-dependent K+ current (IK(Ca)) and high-threshold K+ current independent of Ca2+ (IK(V)). 2. The effect of bath application of the nootropics piracetam and a novel piracetam peptide analog, ethyl ester of N-phenyl-acetyl-L-prolyl-glycine (GVS-111), on these three types of voltage-activated ionic currents was studied. 3. In more than half of the tested cells, ICa was resistant to both piracetam and GVS-111. In the rest of the cells, ICa decreased 19 +/- 7% with 2 mM of piracetam and 39 +/- 14% with 2 microM of GVS-111. 4. IK(V) in almost all cells tested was resistant to piracetam at concentrations up to 2 mM. However, IK(V) in two-thirds of the cells was sensitive to GVS-111, being suppressed 49 +/- 18% with 1 microM GVS-111. 5. IK(Ca) appeared to be the most sensitive current of those studied to both piracetam and GVS-111. Piracetam at 1 mM and GVS-111 at 0.1 microM decreased the amplitude of IK(Ca) in most of the cells examined by 49 +/- 19% and 69 +/- 24%, respectively. 6. The results suggest that piracetam and GVS-111 suppression of voltage-activated calcium and potassium currents of the neuronal membrane may regulate (both up and down) Ca2+ influx into neurons.

PHARMACOLOGICAL ANALYSIS OF THE ACTIVITY OF PHENAZEPAM AND FLUNITRAZEPAM ADMINISTERED IN SUPERLOW DOSES

Benzodiazepine tranquilizers, phenazepam and flunitrazepam, administered to random-bred albino male rats in superlow doses (10−9–10−15 mol/kg), are shown to exert an anxiolytic effect in the conflict test. In contrast to the case with the usual doses, the above effect is not accompanied by marked myorelaxant or sedative effects.

Synthesis and nootropic activity of pyrrolidino[1,2-a]diazacycloalkanes

Previously we have reported on the synthesis and characterization of compounds representing two groups of piracetam analogs, based on pyroglutamic acid [ 1 3 ] and proline [4, 5]. Among the proline-containing compounds possessing nootropic properties, the maximum activity was observed for the ethy i ester of N-pheny lacety lproly Iglycine [6]. In this paper we present data on the synthesis of a new group of the pyracetam analogs, pyrrolidino[1,2-a]diazacycloalkanes, based on the natural pyrrolidine-containing amino acids. We have also studied the antiamnesic activity of the synthesized compounds. We believe that investigation of these compounds, belonging to the class of conformationallyrigid structures, may elucidate the steric requirements of receptors with respect to the nootropic ligand conformation. We have synthesized the following bicyclic derivatives of proline with six, seven, and eight-membered cycles: pyrrolidino[l,2-a]-2,5-diazacyclohexane-l,4-dione (I), pyrrolidino[l,2-a]-2,6-diazacycloheptane-l,5-dione (II), pyrrolidino[1,2-a]-2,7-diazacyclooctane-l,6-dione (III), and 3-carboethoxyethylpyrrolidino[ 1,2-a]-2,5 -diazacyclohexane1,4dione (IV). The bicyclic derivatives of pyroglutamic acid differed by the positions of carbonyl groups in the six-membered cycle, as in pyrrolidino[l,2-a]-2,5-diazacyclohexane1,3,6-trione (V) and pyrrolidino[l,2-a]-2,5-diazacyclohexane-l,4,6-trione (VI), and by the presence of the substituent in the six-membered cycle, as in 2-acetylpyrrolidino[1,2-a]2,5-diazacyclohexane1,4,6-trione (VII).

PIRACETAM AS A CORRECTOR OF THE DELAYED LEARNING DISABILITIES CAUSED BY PRENATAL ALCOHOLIZATION : THE IMPORTANCE OF TIMES OF TREATMENT

The use of piracetam from the 8th to the 20th day of postnatal development prevents disruption of the elaboration of the conditioned bilateral avoidance reflex in the shuttle box in mature male offspring of rats which had received ethanol intragastrally from the 1st to the 20th day of gestation. When used for 13 days one month prior to conditioning, piracetam acts with less efficiency on mature animals, while the same duration of treatment just before conditioning does not affect the impairment of conditioned reflex elaboration.

DEPENDENCE OF THE ANXIOLYTIC EFFECT OF TRANQUILIZERS ON THE LEVEL OF ANXIETY IN A CONFLICT SITUATION

Experiments on random-bred albino rats demonstrate that increasing current strength in a conflict situation abolishes the effects of minor tranquilizers while the effect of potent tranquilizers is preserved at a lower level. These differences are probably due to the differing ability of tranquilizers to compete with endogenous anxiogenic ligands.

Nootropic Drugs in Alzheimer Disease Treatment. New Pharmacological Strategies

Various pharmacological strategies have been employed in the treatment of Alzheimer’s disease (AD): cholinergic enhancers, psychostimulants, vasodilators, neuropeptides, opiate antagonists, nootropics and others (Court and Perry, 1992; Miller et al., 1992). Nootropics (NT) constitute a relatively new group of drugs, which are able to facilitate cognitive functions and prevent impairment of memory, induced by natural and pathological aging, brain insult, trauma, disease and intoxication. These actions are demonstrated in experimental animal models and in human (Vernon and Sorkin, 1991; Voronina, 1992). Piracetam was the first drug presented of this group. At present there has appeared a whole range of new NT in the series of pyrrolidone derivatives (oxiracetam, aniracetam, etiracetam, pramiracetam, nebracetam and etc.) and new substances of nonpyrrolidone structure. The pyrrolidone NT are often recognized as cognitive enhancing agents or “true” NT, because they proved to have none of sedative, stimulant, analeptic, anticonvulsive, myorelaxant properties. Nootropics are used for the treatment of age-related mental decline [normal aging, senile dementia, AD, mental retardation in children, psychoorganic syndromes, cerebrovascular disorders, brain trauma, post stroke, multiple sclerosis, drug abuse (alcohol, cocaine etc.), cerebral ischemia, hypoxic coma, Parkinson’s disease and etc.].

Increased anxiety and reduced pain sensitivity in offspring of rats after prenatal morphinization

Administration of morphine to outbred female rats is shown to result in increased anxiety in the conflict test and reduced pain sensitivity in the tail flick test in 2.5-monthold offspring. In prenatally morphinized offspring the analgetic effect of morphine was enhanced, while the anxiolytic effect of buspirone was lower than in intact animals, which suggests rearrangements in the opioid and serotoninergic systems of the brain.

Behavioral and electrophysiological analysis of anxiolytic effect of mongolian astragalus

Medical herb Mongolian astragalus has anxiolytic activity in conflict situation imposed on random-bred male albino rats, and evokes changes in electroencephalogram which are characteristic of tranquilizers. The drug moderates the τ-rhythm in cerebral hemispheres and hippocampus. In contrast to benzodiazepine tranquilizers, it does not affect the frequencies in other bands.