Design, Synthesis and Anticonvulsant Activity of Cinnamoyl Derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one Oxime.

BACKGROUND: Epilepsy continues to be a significant global health problem and the search for new drugs for its treatment remains an urgent task. 5-HT2 and GABAA-receptors are among promising biotargets for the search for new anticonvulsants. METHODS: New potential 5-HT2 and GABAA ligands in the series of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime were designed using pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out from 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and substituted cinnamoyl chlorides. The anticonvulsant activity of new substances has been established using the maximal electroshock seizure test. RESULTS: Several synthesized substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo [b,d]furan-1-(2H)-one oxime significantly reduced the severity of convulsive manifestations and completely prevented the death of animals after MES. The structure-activity relationship was investigated. The most effective compound was found to be GIZH-348 (1g) (3,4,6,7,8,9-hexahydrodibenzo[ b,d]furan-1(2Н)-one О-(4-chlorophenyl)acryloyl)oxime) at the doses of 10-20 mg/kg. CONCLUSION: Molecular and pharmacophore modelling methods allowed us to create a new group of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime with anticonvulsant activity.

Urokinase-Type Plasminogen Activator Enhances the Neuroprotective Activity of Brain-Derived Neurotrophic Factor in a Model of Intracerebral Hemorrhage.

Brain-derived neurotrophic factor (BDNF) is a classic neuroprotective and pro-regenerative factor in peripheral and central nervous tissue. Its ability to stimulate the restoration of damaged nerve and brain tissue after ischemic stroke and intraventricular hemorrhage has been demonstrated. However, the current concept of regeneration allows us to assert that one factor, even if essential, cannot be the sole contributor to this complex biological process. We have previously shown that urokinase-type plasminogen activator (uPA) complements BDNF activity and stimulates restoration of nervous tissue. Using a model of intracerebral hemorrhage in rats, we investigated the neurotrophic and neuroprotective effect of BDNF combined with uPA. The local simultaneous administration of BDNF and uPA provided effective neuroprotection of brain tissue after intracerebral hemorrhage, promoted survival of experimental animals and their neurological recovery, and decreased lesion volume. The study of cellular mechanisms of the observed neurotrophic effect of BDNF and uPA combination revealed both known mechanisms (neuronal survival and neurite growth) and new ones (microglial activation) that had not been shown for BDNF and uPA. Our findings support the concept of using combinations of biological factors with diverse but complementary mechanisms of action as a promising regenerative approach.

Novel Positive Allosteric Modulators of AMPA Receptors Based on 3,7-Diazabicyclo[3.3.1]nonane Scaffold.

A series of new positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors based on 3,7-diazabicyclo[3.3.1]nonane scaffold have been designed, synthesized, and analyzed. In electrophysiological patch clamp studies, several compounds have demonstrated a sub-nanomolar potency. Compound 4 in in vivo tests showed anti-amnestic properties in the scopolamine-induced model of amnesia in the step-through passive avoidance or maximal electroshock experiments in rats at 0.01 mg/kg showing a significant "dose-response" advantage over memantine. Based on the analysis of the flexible docking results of PAMs, the cyclothiazide-like mechanism of binding mode was suggested as the major site for the interaction with AMPA receptors.

Antidepressant-like effect of fluoxetine may depend on translocator protein activity and pretest session duration in forced swimming test in mice.

The antidepressant-like effect of fluoxetine (20 mg/kg i.p.) has been assessed using the forced swimming test (FST) in IRC (CD-1) mice exposed or not to a pretest session of different duration (5 or 20 min). The influence of the mitochondrial translocator protein (TSPO) activity on the antidepressant-like effect of fluoxetine (20 mg/kg i.p.) in the FST was also studied. The antidepressant-like effect of fluoxetine was observed only in mice subjected to a 5-min pretest session 24 h before the FST. The TSPO antagonist PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; 1 or 3 mg/kg i.p.] inhibited the antidepressant activity of fluoxetine in the FST. In the present study, fluoxetine or PK11195 was administered for a short duration. We suppose that the functional activity of TSPO may depend on a pretest session and that using this procedure is necessary to detect antidepressant activity of fluoxetine-like drugs.

Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles.

The nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons in the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant cause of dementia, and this observation may suggest a possible therapeutic benefit from treatment with NGF. In recent years, convincing data have been published involving neurotrophic factors for the modulation of dopaminergic transmission within the brain and concerning the ability of NGF to prevent the degeneration of dopaminergic neurons. In this connection, the administration of NGF may slow down the progression of Parkinson's disease. However, NGF, as well as other peptidic neurotrophic factors, does not significantly penetrate the blood-brain barrier (BBB) from the circulation. Therefore, any clinical usefulness of NGF as a potential CNS therapy will depend on the use of a suitable carrier system that enhances its transport through the BBB. The present study investigates brain delivery of NGF adsorbed on poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 and the pharmacological efficacy of this delivery system in the model of acute scopolamine-induced amnesia in rats as well as in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian syndrome. As shown by the passive avoidance reflex (PAR) test, the intravenous administration of the nanoparticle-bound NGF successfully reversed scopolamine-induced amnesia and improved recognition and memory. This formulation also demonstrated a significant reduction of the basic symptoms of Parkinsonism (oligokinesia, rigidity, tremor). In addition, the efficient transport of NGF across the BBB was confirmed by direct measurement of NGF concentrations in the murine brain. These results demonstrate that the PBCA nanoparticles coated with polysorbate 80 are an effective carrier system for the transport of NGF to the central nervous system across the BBB following intravenous injection. This approach may improve the NGF-based therapy of age-related neurodegenerative diseases.

Design, synthesis, computational and biological evaluation of new anxiolytics.

New anxiolytics have been discovered by prediction of biological activity with computer programs pass and derek for a heterogeneous set of 5494 highly chemically diverse heterocyclic compounds (thiazoles, pyrazoles, isatins, a-fused imidazoles and others). The majority of tested compounds exhibit the predicted anxiolytic effect. The most potent activity was found in 2-(4-nitrophenyl)-3-(4-phenylpiperazinomethyl)imidazo[1,2-a]pyridine 8, 1-[(4-bromophenyl)-2-oxoethyl]-3-(1,3-dioxolano)-2-indolinone 3, 5-hydroxy-3-methoxycarbonyl-1-phenylpyrazole 5 and 2-(4-fluorophenyl)-3-(4-methylpiperazinomethyl)imidazo[1,2-a]pyridine 7. The application of the computer-assisted approach significantly reduced the number of synthesized and tested compounds and increased the chance of finding new chemical entities (NCEs).

Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.

To discover new cognition enhancers, a set of virtually designed synthesizable compounds from different chemical series was investigated using two computer-aided approaches. One of the approaches is prediction of biological activity spectra for substances (PASS) and the second is prediction of toxicity, mutagenicity, and carcinogenicity (DEREK). To increase the probability of finding new chemical entities, we investigated a heterogeneous set of highly diverse chemicals including different types of heterocycles: five-membered (thiophenes, thiazoles, imidazoles, oxazoles, pyrroles), six-membered (pyridines, pyrimidines), seven-membered (diazepines, triazepines), fused five+six-membered heterocycles (indoles, benzothiazoles, purines, indolizines, neutral, mesoionic, and cationic azolopyridines). A database including 5494 structures of compounds was created. On the basis of the PASS and DEREK prediction results, eight compounds with the highest probability of cognition-enhancing effect were selected. The cognition-enhancing activity testing showed that all of the selected compounds had a pronounced antiamnesic effect and were found to reduce significantly scopolamine-induced amnesia of passive avoidance reflex (PAR). The action of compounds at doses of 1 and 10 mg/kg caused a statistically significant increase in latent time of reflex and in the number of animals, which did not enter the dark chamber when testing the PAR. Therefore, on the basis of computer prediction, new cognition-enhancing agents were discovered within the chemical series, in which this activity was not known previously.