Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers

DM232 (unifiram) and DM235 (sunifiram) are potent cognition-enhancers, which are four order of magnitude more potent than piracetam. These compounds, although not showing affinity in binding studies for the most important central receptors or channels, are able to prevent amnesia induced by modulation of several neurotransmission systems. These compounds are able to increase the release of acetylcholine from rat cerebral cortex, and, as far as unifiram is concerned, to increase the amplitude of fEPSP in rat hippocampal slices. In vitro experiments, performed on hippocampal slices, also supported the hypothesis of a role of the AMPA receptors for the cognition-enhancing properties of unifiram and sunifiram.     

Ginkgo Biloba as a cognitive enhancer

Ginkgo Biloba preparations exhibit nootropic activity in the absence of side effects, which is confirmed by numerous experimental observations and clinical results. The neuroprotector effect of these drugs is based on the antitoxicant action, antioxidant properties, and the ability to normalize the neuromediator and energy transfer mechanisms in cerebral neurons. In this review, recent data on the influence of various Ginkgo Biloba preparations on the cognitive functions in animals and humans and neurochemical mechanisms of the nootropic effect are summarized.     

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

The favorable pharmacological profile exhibited by piracetam stimulated the synthesis of related compounds potentially endowed with a higher nootropic potency. The antiamnesic and procognitive activity of DM232 (unifiram), a new compound structurally related to piracetam, was investigated. Mouse passive avoidance and rat Morris water maze and Social learning tests were employed. DM232 (0.001–1 mg kg^?1 i.p. – 0.01–0.1 1 mg kg^?1 p.o.) prevented amnesia induced by scopolamine (1.5 mg kg^?1 i.p.), mecamylamine (20 mg kg^?1 i.p.), baclofen (2 mg kg^?1 i.p.), and clonidine (0.125 mg kg^?1 i.p.). Furthermore, The antiamnesic effect of the investigated compound was comparable to that exerted by well‐known nootropic drugs such as piracetam (30–100 mg kg^?1 i.p.), aniracetam (100 mg kg^?1 p.o.), rolipram (30 mg kg^?1 p.o.), and nicotine (5 mg kg^?1 i.p). DM232 (0.1 mg kg^?1 i.p.) was also able to prevent amnesia induced by scopolamine (0.8 mg kg^?1 i.p.) in the rat Morris watermaze test. In the rat social learning test, DM232 (0.1 mg kg^?1 i.p.) injected in adults rats reduced the duration of active exploration of the familiar partner in the second session of the test. DM232, similarly to piracetam, reduced the duration of hypnosis induced by pentobarbital. At the highest effective doses, the investigated compound did not impair motor coordination (rota rod test), nor modified spontaneous (Animex). These results indicate DM232 (unifiram) as a novel cognition enhancer, strictly related to piracetam‐like compounds, able to ameliorate memory impairment at doses about 1,000 times lower than the most active available nootropic compounds. Drug Dev. Res. 56:23–32, 2002. © 2002 Wiley‐Liss, Inc.     

A preclinical assessment of d.l-govadine as a potential antipsychotic and cognitive enhancer

Tetrahydroprotoberberines (THPBs) are compounds derived from traditional Chinese medicine and increasing preclinical evidence suggests efficacy in treatment of a wide range of symptoms observed in schizophrenia. A receptor-binding profile of the THPB, d.l-govadine (d.l-Gov), reveals high affinity for dopamine and noradrenaline receptors, efficacy as a D2 receptor antagonist, brain penetrance in the 10-300 ng/g range, and thus motivated an assessment of the antipsychotic and pro-cognitive properties of this compound in the rat. Increased dopamine efflux in the prefrontal cortex and nucleus accumbens, measured by microdialysis, is observed following subcutaneous injection of the drug. d.l-Gov inhibits both conditioned avoidance responding (CAR) and amphetamine-induced locomotion (AIL) at lower doses than clozapine (CAR ED50: d.l-Gov 0.72 vs. clozapine 7.70 mg/kg; AIL ED50: d.l-Gov 1.70 vs. clozapine 4.27 mg/kg). Catalepsy is not detectable at low biologically relevant doses, but is observed at higher doses. Consistent with previous reports, acute d-amphetamine disrupts latent inhibition (LI) while a novel finding of enhanced LI is observed in sensitized animals. Treatment with d.l-Gov prior to conditioned stimulus (CS) pre-exposure restores LI to levels observed in controls in both sensitized animals and those treated acutely with d-amphetamine. Finally, possible pro-cognitive properties of d.l-Gov are assessed with the spatial delayed win-shift task. Subcutaneous injection of 1.0 mg/kg d.l-Gov failed to affect errors at a 30-min delay, but decreased errors observed at a 12-h delay. Collectively, these data provide the first evidence that d.l-Gov may have antipsychotic properties in conjunction with pro-cognitive effects, lending further support to the hypothesis that THPBs are a class of compounds which merit serious consideration as novel treatments for schizophrenia.     

Trypsin as a novel potential absorption enhancer for improving the transdermal delivery of macromolecules

Objectives The aim was to assess the effect of trypsin on the transdermal delivery of macromolecules by applying its specific biochemical properties to the stratum corneum of the skin. Methods Fluorescein isothiocyanate (FITC)‐labelled dextrans (FDs), with molecular weights of 4 to 250 kDa, and FITC‐insulin were used as model macromolecules and a model polypeptide, and the in‐vitro transdermal permeation experiments, with or without trypsin (0.1–2.5%), were carried out using rat skin and cultured human epidermis. The mechanism for the enhancement of trypsin was also studied using fluorescence and conventional light microscopy. Key findings Trypsin significantly increased the transdermal permeability of all FDs through the rat skin (2.0‐ to 10.0‐fold). It also markedly enhanced the permeation of FD4 through three‐dimensional cultured human epidermis (3.1‐fold), which was used to evaluate the transport pathways other than the transfollicular route. Furthermore, the permeation flux of FITC‐insulin was increased by 10.0‐fold with trypsin pretreatment (from 0.02 ± 0.00 to 0.20 ± 0.07 μg/cm² per h). Mechanistic studies indicated that trypsin affects both the intercellular pathway and the hair follicular route, and may alter stratum corneum protein structures, thereby affecting skin barrier properties. Conclusions This study suggests that trypsin could be effective as a biochemical enhancer for the transdermal delivery of macromolecules including peptide and protein drugs.     

2-Methyl-3-phenylaminomethylquinolin-4-one as potential antidepressant with nootropic properties

The new compound, 2-methyl-3-phenylaminomethylquinolin-4-on, belongs to V class of toxicity and exhibits antidepressant and antiamnesic properties. It is established that this compound reduces the duration of immobilization in the test of behavioral despair, prevents from the scopolamine induced amnesia, and exhibits antagonism with reserpine in mice. In a dose of 100 mg/kg, the synthesized compound influences the levels of cerebral catecholamines similarly to imipramine, but with a more pronounced decrease in the level of 5-hydroxytryptamine.     

Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug

Phenibut (beta-phenyl-gamma-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABA(B) and, to some extent, at GABA(A) receptors. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders.     

Prosopis cineraria: A potential nootropic agent

Context: Prosopis cineraria (L.) Druce (Leguminosae), a plant of the Thar Desert of India and Pakistan is used traditionally by local people for the treatment of memory disorders and to arrest wandering of the mind.

Objective: The study includes scientific validation of P. cineraria for nootropic activity. To elucidate the possible mechanism, the anticholinesterase activity was also investigated in different parts of the brain.

Materials and methods: Methanol extract of P. cineraria stem bark (200, 400 and 600 mg/kg body weight p.o.) was administered once in a day for 7 days to rats and these rats were then subjected to Morris water-maze (MWM) test for spatial reference memory (SRM) and spatial working memory (SWM) versions of memory testing. The inhibitory effect of the extract on acetylcholinesterase (AChE) in discrete rat brain regions (prefrontal cortex [PFC], hippocampus [HIP] and amygdala [AMY]) was also investigated using acetyl thiocholine iodide and dithiobisnitrobenzoic acid reagent.

Results and discussion: The oral administrations of methanol extract of P. cineraria in all doses tested, significantly (p < 0.05) improved both spatial reference and working memories in the MWM test in terms of decrease in escape latency during SRM and increase in time spent in the target quadrant during SWM probe trial. A ceiling effect was observed at 400 mg/kg. Pre-treatment for 7 days significantly inhibited the activity of AChE in the HIP, PFC and AMY.

Conclusion: The extract exerted significant nootropic activity in the MWM test which may be attributed to the inhibition of brain AChE.     

Effects of nebracetam (WEB 1881 FU), a novel nootropic, as a M1-muscarinic agonist

We here investigated the effects of nebracetam (WEB 1881 FU 4-aminomethyl-1-benzylpyrrolidin-2-one-hemifumarate), a novel pyrrolidinone nootropic, on the rise of intracellular Ca2+ concentration ([Ca2+]i) in Jurkat cells, a human leukemic T cell line. Nebracetam induced a rise of [Ca2+]i in the medium with 1 mM Ca2+ and without Ca2+ (plus 1 mM EGTA). The nebracetam-induced [Ca2+]i rise was blocked by atropine greater than pirenzepine greater than AF-DX 116. From these results, nebracetam seems to act as an agonist for human M1-muscarinic receptors.     

The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders

Rationale and objectives

Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population.

Results and conclusions

MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.     

MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist-like properties.

1. The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5-(3-fluorophenyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione). 2. The 5-aryl-1,2,4-triazole, MDL 26,479, potently (0.22 +/- 0.05 mg kg-1) inhibited [3H]-flumazenil (Ro15-1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex. 3. Parenteral administration of MDL 26,479 (1 mg kg-1) or the benzodiazepine (BZD) inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg kg-1) increased cortical ex vivo binding of [3H]-hemicholinium-3 ([3H]-HC-3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg-1). 4. MDL 26,479 (20 microM) and DMCM (1 microM) increased excitation in the hippocampal long-term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil. 5. In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo. 6. Previous work showed that MDL 26,479 enhances learning acquisition in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)     

The therapeutic potential of Angiotensin-(1-7) as a novel Renin-Angiotensin System mediator

In this review, we show Angiotensin-(1-7) as a novel Renin Angiotensin System mediator that antagonizes cardiovascular and proliferative effects of Angiotensin II and exerts complex renal actions. We also speculate the possibility of new drugs for the treatment of cardiovascular, genitourinary and hepatic diseases by interfering with ACE2-Angiotensin-(1-7)-Mas axis.     

Monitoring intracellular labile iron pools: A novel fluorescent iron(III) sensor as a potential non-invasive diagnosis tool

The physiological and pathophysiological importance of intracellular redox active "labile" iron has created a significant need for improved noninvasive diagnostic tools to reliably monitor iron metabolism in living cells. In this context, fluorescent iron-sensitive chemosensors in combination with digital fluorescence spectroscopic methods have proven to be highly sensitive and indispensable tools to determine cellular iron homeostasis. Recently, application of fluorescent iron sensors has led to the identification of a complex sub-cellular iron compartmentation. Cell organelle-specific iron sensors will significantly contribute to enhance fundamental knowledge of cellular iron trafficking, representing a crucial prerequisite for the future development of therapeutic strategies in iron dysregulatory diseases. Here we present physicochemical characterization and functional investigation of a new 3-hydroxypyridin-4-one based fluorescent iron(III) sensor, exclusively monitoring labile iron pools in the endosomal/lysosomal compartments. In vitro studies of the fluorescein labeled probe were carried out in murine bone marrow derived macrophages. Endosomal/lysosomal accumulation of the probe was revealed by confocal microscopy. Flow cytometry analyses demonstrated high sensitivity of the probe towards exogenous alterations of intracellular iron concentrations as well as in response to the chelation potency of iron chelators, clinically approved for treatment of iron-overload related diseases.     

A new substance with nootropic activity--N-5(hydroxynicotinoyl)-L-glutamic acid

The psychopharmacological activity of a new compound--ONK-10--N-5(hydroxynicotinoyl)-L-glutamic acid was studied. It was shown in experiments on mice and rats that the compound possesses the pronounced antiamnestic and antihypoxic effects, does not disturb the conditioned reflex activity and the orientation behavior, has no anxiolytic activity and anticonvulsant properties, causes no disorder of movement coordination, is low toxic. ONK-10 is superior by its antiamnestic and antihypoxic effects to piracetam, meclophenoxat, demanol aceglumate and is not inferior to aniracetam.     

3-Amino-1-hydroxypropylidene-1,1-diphosphonate (APD): a novel enhancer of rectal cefoxitin absorption in rats

The promoting action of the calcium chelating compound EDTA on intestinal drug absorption is supposed to be based on Ca2+ depletion, inducing widening of tight junctions. The aim of the present study was to evaluate the effects of the calcium-binding agent 3-amino-1-hydroxypropylidene-1,1-diphosphonate disodium salt (APD) on rectal cefoxitin absorption in rats. The extent of rectal cefoxitin absorption was enhanced by 0.5 to 6% w/v of APD, on rectal infusion as well as on bolus delivery, the latter regimen tending to result in lower bioavailabilities. A maximal cefoxitin bioavailability of 85 +/- 10% was achieved by infusion with 4% w/v of APD, compared with 14 +/- 12% without APD.     

Synthesis of novel MPTP analogs as potential monoamine oxidase B (MAO-B) inhibitors.

The nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetahydropyridine (MPTP) is an excellent substrate and a weak inactivator of the flavoenzyme monoamine oxidase B (MAO-B). In an attempt to develop novel mechanism-based inactivators of MAO-B, we have synthesized analogs of MPTP bearing a variety of functional groups at either the N or the C(4) position and have examined their interactions with a purified MAO-B preparation isolated from beef liver. The substituents selected include allyl, propargyl, ethenyl, ethynyl, and cyclobutyl, that is, functionalities which were considered potential sources of enzyme generated electrophilic or radical intermediates that might alkylate and inactivate the enzyme. None of the C(4)-substituted compounds displayed significant enzyme inhibitor properties although some proved to be good substrates. In the N-substituted MPTP series only the 4-phenyl-1-propargyl analog was a good inhibitor. The time- and concentration-dependent inhibition of MAO-B displayed by this compound is consistent with a mechanism-based inactivation pathway and the catalytic mechanism currently held for monoamine oxidases. The results of these studies provide additional insights into the steric features of the active site of MAO-B and predict that the area in which the C(4) substituent of the tetrahydropyridine ring resides lacks a reactive nucleophilic group.