V. V. Grigoriev

Neuroprotective and cognition-enhancing properties of MK-801 flexible analogs. Structure-activity relationships.

Abstract: Neuroprotective and biobehavioral properties of a series of novel open chain MK‐801 analogs, as well as their structure‐activity relationships have been investigated. Three groups of compounds were synthesized: monobenzylamino, benzhydrylamino, and dibenzylamino (DBA) analogs of MK‐801. It was revealed that DBA analogs exhibit pronounced glutamate‐induced calcium uptake blocking properties and anti‐NMDA activity. The hit compound of DBA series, NT‐1505, was investigated for its ability to improve cognition functions in animal model of Alzheimers disease type dementia, simulated by treating animals with cholinotoxin AF64A. The results from an active avoidance test and a Morris water maze test showed that experimental animals, treated additionally with NT‐1505, exhibited much better learning ability and memory than the control group (AF64A treated) and close to that of the vehicle group of animals (treated with physiological solution). Study of NT‐1505 influence on locomotor activity revealed that it is characterized by a spectrum of behavioral activity radically different from that of MK‐801, and in contrast to the latter one does not produce any psychotomimetic side effects in the therapeutically significant dose interval. The computed docking of MK‐801 and its flexible analogs on the NMDA receptor elucidated the crucial role of the hydrogen bond formed between these compounds and the asparagine residue for magnesium binding in the NMDA receptor. It was suggested that strong hydrophobic interaction between MK‐801 and the hydrophobic pocket in the NMDA receptor‐channel complex determines much higher irreversibility of this adduct compared to the intermediates formed between this site and Mg ions or flexible DBA derivatives, which might explain the absence of PCP‐like side effects of the latter compounds.

Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease

Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.

Study of the neuroprotective action of hybrid structures based on fullerene C60

The neuroprotective action of hybrid structures based on fullerene C60 with attached proline amino acid has been studied. Hybrid structures contained natural antioxidant carnosine or addends with one or two nitrate groups. It has been shown that all studied compounds had antioxidant activity and decreased the concentration of malondialdehyde in homogenates of the rat brain. Compound I, which contained the antioxidant carnosine, has been found to be the most effective antioxidant. All compounds except IV and V inhibited the activity of monoamine oxidase B, while compounds I–IV increased the activity of monoamine oxidase A. All investigated compounds inhibited glutamate-induced Ca2+ uptake into synaptosomes of the rat brain cortex. Compound III, containing two nitrate groups, has been found to be the most effective inhibitor. This compound caused a significant increase of the currents of AMPA receptors (AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid).

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

Synthesis and biological activity of N-substituted tetrahydro-γ-carbolins bearing bis(dimethylamino)phenothiazine moiety

An approach for modification of biologically active N-substituted tetrahydro-γ-carbolines with bis(dimethylamino)phenothiazine moiety via the CsF-catalyzed reaction of γ-carbolines with 1-[3,7-bis(dimethylamino)phenothiazin-10-yl]propenone was developed. Effects of the synthesized compounds on neuronal NMDA receptors were examined by radioligand binding assay.

Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice

Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6J at 1 or 5mg/kg, ip) with new derivatives of isothiourea (0.5-1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC₅₀ values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance.

Modification of biologically active amides and amines with fluorine-containing heterocycles 8. γ-Carbolines modified with the 2-(2-trifluoromethylimidazo[1,2-a]pyridin-6-yl)ethyl fragment

An approach to modification of biologically active g-carbolines with the 2-(2-trifluoromethylimidazo[1,2-a]pyridin-6-yl)ethyl fragment was proposed. The modification involves a reaction of 2-trifluoromethyl-6-vinylimidazo[1,2-a]pyridine with g-carbolines. The effect of the compounds obtained on neuronal NMDA receptors was studied by the radioligand binding method.

Binary Mechanism of Action of Cognition Enhancer NT1505 on Glutamate Receptors

Compound NT1505 potentiates AMPA receptors in rat brain neurons and simultaneously noncompetitively blocks NMDA receptors via two different mechanisms. Considering previously obtained data on strong cognition-enhancing properties of this compound we can conclude that NT1505 is a novel cognition stimulator exhibiting properties of a positive modulator of AMPA receptors and a blocker NMDA receptor.

Reconnaissance paleomagnetism of Late Triassic blocks, Kuyul region, Northern Kamchatka Peninsula, Russia

The northernmost Kamchatka Peninsula is located along the northwestern margin of the Bering Sea and consists of complexly deformed accreted terranes. Progressing inland from the northwestern Bering Sea, the Olyutorskiy, Ukelayat and Koryak superterranes (OLY, UKL and KOR) are crossed. These terranes were accreted to the backstop Okhotsk-Chukotsk volcanic-plutonic belt (OChVB) in northernmost Kamchatka. A sedimentary sequence of Albian to Maastrichtian age overlaps the terranes and units of the Koryak superterrane, and constrains their accretion time. A paleomagnetic study of blocks within the Kuyul (KUY) terrane of the Koryak superterrane was completed at two localities (Camp 2: λ=61.83°N, φ=165.83°E and Camp 3: λ=61.67°N, φ=164.75°E). At both localities, paleomagnetic samples were collected from Late Triassic (225–208 Ma) limestone blocks (2–10 m in outcrop height) within a melange zone. Although weak in remanent magnetization, two components of remanent magnetization were observed during stepwise thermal demagnetization at 32 sites. The A component of magnetization was observed between room temperature and approximately 250 °C. This magnetic component is always of downward directed inclination and shows the best grouping at relatively low degrees of unfolding. Using McFadden–Reid inclination-only statistics and averaging all site means, the resulting A component mean is Iopt=60.3°, I95=5.0° and n=36 (sites). The B magnetic component is observed up to 565 °C, at which temperature, most samples have no measurable remanent magnetization, or growth of magnetic minerals has disrupted the thermal demagnetization process. Combining sites with Fisher estimates of kappa (k-value)≥13 and n (sites)≥3, where bedding orientation differs within a block, most of these sites show the best grouping of B component directions at 100% unfolding, and two of the blocks display remanent magnetizations of both upward and downward directed magnetic inclination. Combining sites with Fisher estimates of kappa (k-value)≥13 and n (sites)≥3, the resulting overall B component paleolatitude and associated uncertainty are λobs=30.4°N or S, λ95=8.9° and n=19 (sites). When compared with the expected North America paleolatitude of λAPWP expected=57.9°N, our data support a model in which blocks within the Koryak superterrane are allochthonous and far travelled.

Calcium-dependent chloride current in rat cerebellar Purkinje cell membranes

The presence of calcium-dependent potential-activated chloride currents in the membranes of freshly isolated rat cerebellar Purkinje cells (12–15 days) was shown by the whole-cell patch clamp technique. Chloride currents appeared in a sodium-free external solution and reversibly disappeared in the absence of external chloride and calcium ions.