Stereodynamics of some pyridoxine derivatives

Copyright © 2016 John Wiley & Sons, Ltd.The conformational properties of three pyridoxine derivatives were studied by 1H dynamic NMR spectroscopy. Conformational exchange caused by a rotation of 2-nytrophenyl group around one single C–C bond, of 2,4-dinitrophenyl substituent around two single C–O bonds, and twist-twist transformations of the seven-membered ketal cycle was observed by NMR experiments at low temperatures. Meanwhile, the conformational exchange of the acetal ring remains fast in the NMR timescale even at 198 K. The energy barriers for all observed conformational exchange processes were determined by the lineshape analysis of dynamic NMR spectra. The activation barriers of the 2-nitrophenyl group rotation were almost the same for all studied compounds, about 40–41 kJ/mol. The energy barriers of the conformational exchange processes of the 2,4-nitrophenyl group and the ketal cycle increased significantly up to 10 kJ/mol in comparison with previously studied compounds with similar structure. Copyright © 2016 John Wiley & Sons, Ltd

Stereodynamics of some pyridoxine derivatives

© 2016 John Wiley & Sons, Ltd.The conformational properties of three pyridoxine derivatives were studied by 1H dynamic NMR spectroscopy. Conformational exchange caused by a rotation of 2-nytrophenyl group around one single C-C bond, of 2,4-dinitrophenyl substituent around two single C-O bonds, and twist-twist transformations of the seven-membered ketal cycle was observed by NMR experiments at low temperatures. Meanwhile, the conformational exchange of the acetal ring remains fast in the NMR timescale even at 198K. The energy barriers for all observed conformational exchange processes were determined by the lineshape analysis of dynamic NMR spectra. The activation barriers of the 2-nitrophenyl group rotation were almost the same for all studied compounds, about 40-41kJ/mol. The energy barriers of the conformational exchange processes of the 2,4-nitrophenyl group and the ketal cycle increased significantly up to 10kJ/mol in comparison with previously studied compounds with similar structure

Novel potent pyridoxine-based inhibitors of AChE and BChE, structural analogs of pyridostigmine, with improved in vivo safety profile

© 2016 Elsevier LtdWe report a novel class of carbamate-type ChE inhibitors, structural analogs of pyridostigmine. A small library of congeneric pyridoxine-based compounds was designed, synthesized and evaluated for AChE and BChE enzymes inhibition in vitro. The most active compounds have potent enzyme inhibiting activity with IC50 values in the range of 0.46–2.1 μM (for AChE) and 0.59–8.1 μM (for BChE), with moderate selectivity for AChE comparable with that of pyridostigmine and neostigmine. Acute toxicity studies using mice models demonstrated excellent safety profile of the obtained compounds with LD50 in the range of 22–326 mg/kg, while pyridostigmine and neostigmine are much more toxic (LD50 3.3 and 0.51 mg/kg, respectively). The obtained results pave the way to design of novel potent and safe cholinesterase inhibitors for symptomatic treatment of neuromuscular disorders

Pathophysiological Mechanisms of Antipsychotic-Induced Parkinsonism

Among neurological adverse reactions in patients with schizophrenia treated with antipsychotics (APs), drug-induced parkinsonism (DIP) is the most common motility disorder caused by drugs affecting dopamine receptors. One of the causes of DIP is the disruption of neurotransmitter interactions that regulate the signaling pathways of the dopaminergic, cholinergic, GABAergic, adenosinergic, endocannabinoid, and other neurotransmitter systems. Presently, the development mechanisms remain poorly understood despite the presence of the considered theories of DIP pathogenesis

Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia

Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically “non-dopamine” Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of “non-dopamine” Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS

Ритмическая транскраниальная магнитная стимуляция в терапии нейропатической боли, сопровождающейся коморбидной депрессией: обзор эффективных параметров лечебных протоколов

Neuropathic pain affects 7 % of the general population worldwide, it is often resistant to analgesic treatments and is complicated with depressive states in 57–65 % of this patients’ cohort. Ongoing research of current therapeutic approaches, including repetitive transcranial magnetic stimulation (rTMS) use in neuropathic pain and depression, grants new data about the details of treatment protocols’ designs. The aim of our literature review was to evaluate those parameters of the treatment protocols which proved significant efficacy in the management of the neuropathic pain with comorbid depression.Focusing on the Scopus, Elsevier and PubMed databases search, we have found 639 peer‑review articles. 23 studies have been included into the data analysis, whereas others were excluded based on their heterogeneous study design. Across the data analysis we evaluated such rTMS parameters as the type of a coil, type of stimulation area, locus of gained evoked motor potential, amplitude of stimulation, duration of session, frequency/number of sessions per day/month, tie duration between sessions, number and frequency of trains, amount and frequency of pulses containing and efficacy of treatment. Those studies that performed repetitive transcranial magnetic stimulation using the figure‑of‑8 coil over the M1 brain area, for 10 or more daily sessions with duration from 7 up to 40 minutes, of 10–20 Hz frequency, intensity 80–90 % of resting motor threshold and total pulses number over 1500 per session demonstrated the greater efficacy in pain level decrease and depression scores reduction among neuropathic pain patients with comorbid depression. Conducting an additional maintenance phase of treatment prolonged the therapeutic effect of the course.Based on the data review, the parameters of the most efficient rTMS protocols’ designs in management of patients with neuropathic pain and comorbid depression have been revealed. Further research requires investigation of other promising indicators of rTMS efficacy use in neuropathic pain with comorbid depression, such as stimulation over multiple brain areas, the duration/timing of additional maintenance phase of treatment, and the figure‑of‑8 coil orientation options.По общемировым данным, нейропатическая боль встречается у 7 % населения и в 57–65 % случаев сопровождается коморбидной депрессией, что, в свою очередь, усугубляет течение болезни и ухудшает качество жизни пациентов. Ритмическая транскраниальная магнитная стимуляция (рТМС) представляет собой неинвазивный нефармакологический метод терапии депрессии,  также способный помочь пациентам облегчить восприятие нейропатической боли. Представлен обзор результатов применения протоколов рТМС, продемонстрировавших эффективность в терапии клинических состояний, сопровождающихся нейропатической болью с коморбидной депрессией.Исследуя базы данных Scopus, Elsevier и PubMed , мы обнаружили 639 статей, из которых в соответствии с критериями включения были отобраны 23. Оценке подверглись данные о клинической эффективности рТМС в терапии нейропатической боли и коморбидной депрессии в зависимости от параметров протокола стимуляции, включая тип катушки, целевую зону мозга, продолжительность сеанса, частоту/количество сеансов в день/месяц, а также межсеансовые интервалы, число и частоту импульсов.Протоколы, показавшие наибольшую эффективность, включали такие параметры, как использование катушки в форме восьмерки, направленной на первичную моторную зону (M1), применение рТМС в течение не менее 10 ежедневных сеансов, использование высокочастотной стимуляции (10–20 Гц) с интенсивностью 80–90 % от порога моторного ответа, с длительностью сессии от 7 до 40 мин и с общим количеством импульсов не менее 1500 за сеанс. Проведение дополнительной поддерживающей фазы лечения продлевало терапевтический эффект курса.Результаты анализа данных литературы предполагают, что определенная комбинация параметров стимуляции может быть более эффективной для терапии нейропатической боли, сопровождающейся коморбидной депрессией, тем самым открывая новые возможности терапии для пациентов с резистентными состояниями, плохо поддающимися фармакологической коррекции. Рассмотрение параметров протоколов рТМС выявило необходимость дальнейшего изучения метода в лечении указанных клинических состояний не только в рамках репликации данных, но и для анализа таких дополнительных параметров, как последовательная или одновременная стимуляция нескольких областей мозга, угол поворота катушки, а также для уточнения времени поддерживающей фазы стимуляции

Reversible temperature-responsible emission in solutions within 293–333 K produced by dissociative behavior of multinuclear Cu(I) complexes with aminomethylphosphines

© 2019 Elsevier B.V. A series of multinuclear Cu(I) complexes (CuI)xLy, namely the previously reported (CuI)6L2 and (CuI)2L′ and novel (CuI)2L2, where L and L′ are 1,5-di(R)-3,7-bis(2-pyridine-2′-yl)ethyl-1,5-diaza-3,7-diphosphacyclooctanes are introduced. Both dissociative and oxidative behavior of the complexes in DMSO and DMF solutions are correlated with the time-dependent changes in their phosphorescence originated from 3(X + M)LCT transitions. The instability of butterfly-like (CuI)2L′ resulting in its oxidative degradation in DMSO and transformation into (CuI)L′2 in DMF solutions differentiates it from more stable linear complexes (CuI)6L2 and (CuI)2L2. The complexes (CuI)2L2 and (CuI)L2 produced by the dissociation of (CuI)6L2.in DMSO and DMF solutions are regarded as structural motifs responsible for both reversible blue-shifting by 10 nm of the emission band and the decrease in the excited states lifetime values upon the heating of the solutions within 293–333 K. This temperature-induced behavior along with the phosphorescence character of the emission of both complexes points to thermally activated delayed fluorescence as the reason for the reversible temperature-induced spectral changes of hexanuclear (CuI)6L2. Smaller nuclearity of (CuI)2L2 is the reason for partial reversibility of the spectral changes

Stereodynamics of some pyridoxine derivatives

© 2016 John Wiley & Sons, Ltd.The conformational properties of three pyridoxine derivatives were studied by 1H dynamic NMR spectroscopy. Conformational exchange caused by a rotation of 2-nytrophenyl group around one single C-C bond, of 2,4-dinitrophenyl substituent around two single C-O bonds, and twist-twist transformations of the seven-membered ketal cycle was observed by NMR experiments at low temperatures. Meanwhile, the conformational exchange of the acetal ring remains fast in the NMR timescale even at 198K. The energy barriers for all observed conformational exchange processes were determined by the lineshape analysis of dynamic NMR spectra. The activation barriers of the 2-nitrophenyl group rotation were almost the same for all studied compounds, about 40-41kJ/mol. The energy barriers of the conformational exchange processes of the 2,4-nitrophenyl group and the ketal cycle increased significantly up to 10kJ/mol in comparison with previously studied compounds with similar structure