Antiepileptic Activity of a New Derivative of Benzimidazole RU-1205

Spasov, A. A.; Kalitin, K. Yu.; Grechko, O. Yu.; Anisimova, V. A.

doi:10.1007/s10517-016-3164-1

Cited by 4 publications

(2 citation statements)

References 10 publications

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“…Our research focuses on the new kappa-opioid agonist RU-1205. Unlike classical representatives of this class, the compound RU-1205 exhibits pronounced analgesic, anticonvulsant [11, 12] and neuroprotective [13] effects while not causing dysphoric or aversive effects. This property may be due to functional selectivity, or the presence of an additional mechanism of action that is associated with blocking p38 mitogen-activated protein kinase (MAPK), since it was previously shown that the p38 inhibitor SB203580 can completely eliminate the aversive effect of kappa-opioid agonists [14].…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Kalitin,

Mukha,

Spasov

2024

Preprint

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This study focuses on RU-1205, a new kappa-opioid agonist exhibiting analgesic effect without causing dysphoric or aversive reactions. It is assumed that the absence of dysphoric or aversive effects can be attributed to functional selectivity or it might be due to an additional mechanism of action that involves blocking the p38 mitogen-activated protein kinase (MAPK). The aim of this study was the experimental identification of the mechanisms of action of RU-1205 associated with inhibition of MAPK p38 and functional selectivity at kappa-opioid receptors. Materials and methods: Rats weighing 260-280 g were implanted with chronic cortical and deep electrodes. LFP activity was recorded after intracerebroventricular administration of well-studied reference substances: the selective kappa-opioid agonist U-50488 at a dose of 100 μg; the MAPK p38 blocker SB203580 at a dose of 1 μg; and the investigational compound RU-1205 at 350 μg. The weighted phase lag index (WPLI) was calculated. Subsequently, machine learning techniques were employed to reduce dimensionality and extract connectivity features using the principal component analysis method. Finally, signal classification was conducted using models based on Gaussian processes. By applying the patch-clamp technique in the whole-cell configuration, the spike activity of pyramidal neurons in the basolateral amygdala was studied. The neurons were identified by their accommodation properties. After local perfusion of the test compounds, 3 dose-response curves were obtained for: (1) U-50488 at concentrations ranging from 0.001 to 10 μM; (2) combinations of U-50488 (0.001-10 μM) and RU-1205 (10 μM); and (3) combinations of U-50488 (0.01-10 μM) and RU-1205 (100 μM). Results: The developed models were able to classify the compound RU-1205 as a "non-inhibitor" of MAPK p38 with a probability of 0.89. The results obtained were confirmed in patch clamp experiments on acute brain slices, where it was demonstrated that U-50488 statistically significantly increases the spike activity of pyramidal neurons in the basolateral amygdala (p <0.05) and RU-1205 interacts with U-50488, suppressing its effect on the spike activity of neurons. Conclusions: The findings suggest that compound RU-1205 displays properties consistent with a functional kappa opioid receptor agonist and does not have a significant effect on MAPK p38. The study demonstrates the possibility of integrating electrophysiological measurements and advanced data analysis methods for a deep understanding of neuronal mechanisms of drug action and underscores the potential for further research in this area.

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Section: Introductionmentioning

confidence: 99%

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Kalitin,

Mukha,

Spasov

2024

Preprint

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“…Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research [1]. Numerous compounds containing benzimidazole moieties have been reported to exhibit diverse biological and pharmacological properties which include, but not limited to, antitumor [2], anticancer [3], antimalarial [4], anti-inflammatory [5], antiepileptic [6], antitubercular [7], anti-HIV [8], antihypertensive [9], antimicrobial [10], anthelmintic [11], antioxidant [12] and anti-diabetic [13] activities. Conventionally, a drug is designated by its dominant or by its first recognized function; hence, benzimidazole nucleus is the core structure of several drugs such as bendamustine as anticancer; omeprazole as anti-ulcer; albendazole as anthelmintic, benomyl as antifungal; telmisartan as antihypertensive; astemizole as receptor antagonist drugs [14].…”

Section: Introductionmentioning

confidence: 99%

Facile synthesis of N substituted 2 3 5 dinitrophenyl benzimidazole derivatives for antimicrobial investigation

Aderohunmu¹,

Ajani²,

Tolu-Bolaji³

et al. 2017

Seventh International Conference on Advances in Applied Science and Environmental Engineering - ASEE 2017

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Benzimidazole derivatives are crucial structural heterocyclic motifs found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. 2-(3,5-Dinitrophenyl) benzimidazole, 1 was synthesized by [4+1]-cycloaddition of o-phenylenediamine with 3,5dinitrobenzoic acid in catalytic amount of NH 4 Cl. Compound 1 was subsequently utilized as precursor which upon reaction with some halogenated molecular entity furnished the targeted N-substituted-2- (3,5-dinitrophenyl) benzimidazole derivatives in improved yields after reaction optimization engagement. The progress of reaction was monitored with TLC and the chemical structures were confirmed by analytical data and spectroscopic means such as UV, IR, mass spectra, 1 H NMR, 13 C NMR and DEPT-135. The titled compounds were screened for their antimicrobial activity alongside with gentamicin standard drug, using agar diffusion method while the minimum inhibitory concentration (MIC) was carried out using serial dilution method. The result showed that the synthetic method used herein was successful for the preparation of the titled benzimidazole motifs in high yields and eco-friendly manner. The compounds showed broad spectrum of activity and most of them competed favourably with gentamicin and they exhibited highly promising antibacterial potential for future drug development. They are good candidates for further studies in term of SAR study and other pharmacological screenings essential in therapeutic research.

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Electrophysiological effects of kappa-opioid analgesic, RU-1205, using machine learning methods

Kalitin,

Mukha,

Spasov

2024

Farm. farmakol. (Pâtigorsk)

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The study is focused to the investigation of a new kappa-opioid agonist RU-1205, which exhibits an analgesic effect without causing dysphoric or aversive actions. It is assumed that this effects may be due to its functional selectivity, or the presence of an additional mechanism of action that involves blocking p38 mitogen-activated protein kinase (MAPK).The aim of the study was an experimental identification of RU-1205 mechanisms of action associated with the inhibition of MAPK p38 and functional selectivity for kappa opioid receptors.Materials and methods. The LFP activity was recorded in the male rats weighing 260–280 g (n=62) and implanted with chronic cortical and deep electrodes, after the intracerebroventricular administration of the well-studied reference substances: the selective kappa-opioid agonist U-50488 100 μg; the MAPK p38 blocker SB203580 1 μg; and the investigational compound RU-1205 at 350 μg. The weighted phase lag index (WPLI) was calculated. Subsequently, machine learning methods were employed to reduce the dimensionality and extract connectivity features using the principal component analysis method, then a signal classification was performed (models based on Gaussian processes). Using the local patch-clamp technique in the “whole-cell” configuration, the spike activity of pyramidal neurons in the basolateral amygdala was studied. Neurons were identified by their accommodation properties. After local perfusion of the test compounds, 3 dose-response curves were obtained for: (1) U-50488 at concentrations ranging from 0.001 to 10 μM; (2) combinations of U-50488 (0.001–10 μM) and RU-1205 (10 μM); and (3) the combinations of U-50488 (0.01–10 μM) and RU-1205 (100 μM).Results. The developed models made it possible to classify the compound RU-1205 as a “non-inhibitor” of MAPK p38 with a high probability. The results obtained were confirmed in patch-clamp experiments on acute brain slices where it was demonstrated that U-50488 statistically significantly increases the spike activity of pyramidal neurons of the basolateral amygdala (p <0.05), and RU-1205 interacts with U-50488, competitively suppressing its effect on the spike activity of neurons.Conclusion. The findings suggest that compound RU-1205 displays properties consistent with a functional kappa agonist activity and does not have a significant effect on MAPK p38. The study demonstrates the possibility of integrating electrophysiological measurements and advanced data analysis methods for a deep understanding of drug action and underscores the potential for further research in this area.

show abstract

Antiepileptic Activity of a New Derivative of Benzimidazole RU-1205

Cited by 4 publications

References 10 publications

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Facile synthesis of N substituted 2 3 5 dinitrophenyl benzimidazole derivatives for antimicrobial investigation

Electrophysiological effects of kappa-opioid analgesic, RU-1205, using machine learning methods

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