The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors.

BACKGROUND AND PURPOSE: Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. EXPERIMENTAL APPROACH: E1R was tested for sigma receptor binding activity in a [³H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca²âº concentration ([Ca²âº](i)) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. KEY RESULTS: Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca²âº](i) increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. CONCLUSION AND IMPLICATIONS: E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases.

Recent trends in the design, synthesis and biological exploration of ß-lactams.

Since the discovery of penicillin, natural and synthetic ß-lactams have aroused great interest not only as sources of effective antibacterial agents but also as specific inhibitors of proteases responsible for various non-bacterial pathological processes. This interest was reflected in our review published in Current Medicinal Chemistry in 2003. The present article summarises new data published during the last decade dedicated to the design, synthesis and biological exploration of new ß-lactams with anti-inflammatory, antiviral, anticancer and other activities based on the inhibition of human leukocyte elastase, porcine pancreatic elastase, tryptase, chymase, human cytomegalovirus protease, fatty acid amide hydrolase, protein phosphatase methylesterase-1, serine protease responsible for tumor proliferation, cysteine proteases, matrix metalloproteinases, human 20s proteasome, human immunodeficiency virus, cholesterol absorption, human fatty acid synthase, bacterial RNase A and Leishmania D-mannosyl phosphate transferase. Antitumor effect was achieved also by new ß-lactams activating apoptosis-specific poly(ADP-ribose) polymerase or participating in DNA intercalation.

Separation of piracetam derivatives on polysaccharide-based chiral stationary phases.

High-performance liquid chromatography was used for the enantiomeric separation of two chiral piracetam derivatives. The suitability of six commercially available polysaccharide-based chiral stationary phases (CSPs) under normal phase mode for direct enantioseparation has been investigated. The influence of the CSPs as well the nature and content of an alcoholic modifier in the mobile phase on separation and elution order was studied. It was established that CSP Lux Amylose-2 shows high chiral recognition ability towards 4-phenylsubstituted piracetam derivatives.

Synthesis and antitumor activity of selected 7-alkylidene substituted cephems.

Selected 7-alkylidene substituted cephems were synthesized and subjected to antitumor assay. The effect of substituents was examined to establish structure-activity relationships. It was found that the intensive intracellular generation of nitric oxide induced by tert-butyl 7-alkylidene cephalosporanate sulfones could be also regarded as an additional cytotoxic factor taking place both in vitro and in vivo experiments.

[Hydrolysis of the amidine analogs of penicillins]. / Gidroliz amidinovykh analogov penitsillinov.

The products of the hydrolytic degradation of 6-beta-(hexahydro-IH-azepenyl-1)methylenamino) penicillanic acid, 6-beta-(N,N-dimethylformamidino-N1)-penicillanic acid and 6-beta-(morpholinyl-1)methylenamino penicillanic acid were identified with the method of thin-layer chromatography and paper electrophoresis in neutral, acid and alkaline solutions and in the presence of penicillinase. The data of the study showed that acid hydrolysis of the amidine analogues of penicillins resulted in cleavage of the beta-lactame cycle and formation of the respective penicillanic acids. In the alkaline medium the secondary amine (hexamethylenimine, dimethylamine, morpholine) was cleaved from the antibiotic side chain and the resulting N-formyl-6-aminopenicillanic acid was further cleaved up to peniciec acid. The beta-lactame cycle of the antibiotics was cleaved under the effect of penicillinase and the resulting penicilloinic acids degraded into peniciec acid, N-formylpeniciec acid and secondary amines. In the nutral solution the antibiotics were transformed into N-formyl-6-aminopenicillanic acid and penicilloinic acids at the first stage of the hydrolysis followed by their further degradation with formation of N-formylpeniciec acid, peniciec acid and secondary amines.

[Derivatographic analysis of 6-beta-[(hexahydro-1H-azepin-1-yl) methylenamino]penicillanic acid]. / Derivatograficheskii analiz 6-beta[(geksagidro-1H-azepin-1-il) metilenamino]penitsillanovoi kisloty.

Derivatographic analysis of 5 samples of 6-beta-(hexahydro-IH-azepin-I-yl)methylenamino penicillanic acid was performed. In addition to the antibiotic the samples had water and acetone in their composition. No effects associated with changes in the physical and chemical state of the substance were observed on the derivatogramme of the samples containing 0.2 and 0.8 per cent of water up 140 degrees C. With a further increase in the temperature an exothermic effect was observed with maximum at 152--153 degrees C connected with melting and chemical degradation of the substance. The derivatogrammes of the samples containing 89--96.4 per cent of the antibiotic were characterized by an endothermic effect with minimum at 65 degrees C caused by evaporation of acetone and partially water from them and by an exothermic effect with maximum at 120 degrees C practically not accompanied by any change in the weight resulting from chemical interaction of the antibiotic with water. The study showed sensitivity of 6-beta-(hexahydro-IH-azepin-I-yl)methylenaminopenicillanic acid to the presence of even insignificant amounts of water in it, maximum elimination of which from the antibiotic is an important factor of increasing its stability.

[Stability of the amidine analogs of penicillin and deacetoxycephalosporin to the penicillinase of Bacillus licheniformis 749/c]. / Ustoichivost' amidinovykh analogov penitsillina i dezatsetoksitsefalosporina k penitsillinaze Bacillus licheniformis 749/c

Fermentative hydrolysis of 3 derivatives of 6-beta-amidinopenicillanic acid and I derivative of 7-beta-amidinodeacetoxycephalosporanic acid by penicillinase produced by Bacillus licheniformis 749/c was studied. It was found that 6-beta-[(hexahydro-IH-azepin-I-yl) methyleneamino] penicillanic acid, 6-beta-(N1 N-dimethylformamidino-N1) penicillanic acid and 6-beta [(morpholin-I-yl) methylenemino] penicillanic acid were hydrolyzed by the enzyme 50, 70, and 160 times respectively slower than benzylpenicillin. 7-beta-[(Hexahydro-IH-azepin-I-yl)' methylenemino] deacetoxycephalosporanic acid proved to be at least 10 times more stable to the effect of penicillinase than methicillin. In addition unlike the amidine analogues of penicillin the above compound had an inhibitory effect on penicillinase produced by Bacillus licheniformis 749/c.

[Stability of 6-beta-[(hexahydro-1H-azepin-l-yl)methyleneamino]-penicillanic acid in aqueous solutions]. / Ustoichivost'6-beta[(geksagidro-1H-azepin-l-il)metilenamino]penitsillanovoi kisloty v vodnykh rastvorakh

Stability of acqueous solutions of 6-beta-[(hexahydro-IH-azepin-I-yl)methylenamino] penicillanic acid at various values of pH and temperature was studied. It was found that inactivation of the antibiotic in both the acid and the alkaline medium proceeded according to the equation of the 1st order. At pH 1.3 and a temperature of 35 degrees the half life of the antibiotic was 7 hours. The activation energy calculated according to the Arrenius equation was 13.5 kcal/mol at pH 1.3 and 22.2 kcal/mol at pH 10.5. The antibiotic was inactivated in glycol and phosphate buffers. Its qualitative analysis was performed according to an improved iodometric method.