Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the treatment of neuropathic pain and pruritus syndromes due to interaction with the secondary molecular targets. Our own clinical studies have identified antipruritic and/or analgesic efficacy of the following compounds: tianeptine (atypical tricyclic antidepressant), citalopram (selective serotonin reuptake inhibitor), mianserin (tetracyclic antidepressant), carbamazepine (anticonvulsant), trazodone (serotonin antagonist and reuptake inhibitor), and chlorprothixene (antipsychotic). Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is known to have an analgesic effect too. The mechanism of such effect of these drugs is not fully understood. Herein we review and correlate the literature data on analgesic/antipruritic activity with pharmacological profile of these compounds.

Human serum albumin (HSA) is an endogenous inhibitor of angiotensin I-converting enzyme (ACE) and, thus, plays a key role in the renin–angiotensin–aldosterone system (RAAS). However, little is known about the mechanism of interaction between these proteins, and the structure of the HSA–ACE complex has not yet been obtained experimentally. The purpose of the presented work is to apply computer modeling methods to study the interaction of HSA with ACE in order to obtain preliminary details about the mechanism of their interaction. Ten possible HSA–ACE complexes were obtained by the procedure of macromolecular docking. Based on the number of steric and polar contacts between the proteins, three leading complexes were selected, the stabilities of which were then tested by molecular dynamics (MD) simulation. Based on the results of MD simulation, the two most probable conformations of the HSA–ACE complex were selected. The analysis of these conformations revealed that the processes of oxidation of the thiol group of Cys34 of HSA and the binding of albumin to ACE can reciprocally affect each other. Known point mutations in the albumin molecules Glu82Lys, Arg114Gly, Glu505Lys, Glu565Lys and Lys573Glu can also affect the interaction with ACE. According to the result of MD simulation, the known ACE mutations, albeit associated with various diseases, do not affect the HSA–ACE interaction. A comparative analysis was performed of the resulting HSA–ACE complexes with those obtained by AlphaFold 3 as well as with the crystal structure of the HSA and the neonatal Fc receptor (FcRn) complex. It was found that domains DI and DIII of albumin are involved in binding both ACE and FcRn. The obtained results of molecular modeling outline the direction for further study of the mechanisms of HSA–ACE interaction in vitro. Information about these mechanisms will help in the design and improvement of pharmacotherapy aimed at modulation of the physiological activity of ACE.

Bemethyl is an actoprotector, an antihypoxant, and a moderate psychostimulant. Even though the therapeutic effectiveness of bemethyl is well documented, there is a gap in knowledge regarding its metabolic products and their quantitative and qualitative characteristics. Since 2018, bemethyl is included to the Monitoring Program of the World Anti-Doping Agency, which highlights the challenge of identifying its urinary metabolites. The objective of the study was to investigate the biotransformation pathways of bemethyl using a combination of liquid chromatography-high-resolution mass spectrometry and in silico studies. Metabolites were analyzed in a 24 h rat urine collected after oral administration of bemethyl at a single dose of 330 mg/kg. The urine samples were prepared for analysis by a procedure developed in the present work and analyzed by high performance liquid chromatography–tandem mass spectrometry. For the first time, nine metabolites of bemethyl with six molecular formulas were identified in rat urine. The most abundant metabolite was a benzimidazole–acetylcysteine conjugate; this biotransformation pathway is associated with the detoxification of xenobiotics. The BioTransformer and GLORY computational tools were used to predict bemethyl metabolites in silico. The molecular docking of bemethyl and its derivatives to the binding site of glutathione S-transferase has revealed the mechanism of bemethyl conjugation with glutathione. The findings will help to understand the pharmacokinetics and pharmacodynamics of actoprotectors and to improve antihypoxant and adaptogenic therapy.

This article reports the results of the study of side effects of selective sodium-calcium exchange blocker KB-R7943 used as an analgesic drug in rats with streptozotocin-induced type 1 diabetes mellitus. ECG analysis showed no negative effect of KB-R7943 on the cardiovascular system of control rats and rats with type 1 diabetes mellitus. In open field testing, the behavior (motor activity and signs of anxiety) of rats did not change after the administration of KB-R7943. The tissues of the hippocampus and hypothalamus were analyzed for the level of the gene expression of the voltage-gated sodium channel Nav1.7 (SCN9A), the α2δ-1 subunit of voltage-gated T-type calcium channels (CACNA2D1), Bax and Bcl-2 involved in the pathogenesis of diabetic neuropathy. It was shown that in the hippocampus of rats with DM1, the administration of KB-R7943 led to an increase in CACNA2D1 expression and a decrease in SCN9A expression, while in the control group the level of Nav1.7 mRNA increased under the influence of the drug. The expression of both Bax and Bcl-2 in the hippocampus of control animals after the administration of KB-R7943 increased. In the hypothalamus of the diabetic group, KB-R7943 therapy reduced the level of Bcl-2 mRNA, leaving the level of Bax expression unchanged. Работа посвящена исследованию побочных эффектов применения селективного блокатора натрий-кальциевого обменника KB-R7943 как противоболевого препарата у крыс со стрептозотоцин-индуцированным сахарным диабетом 1-го типа. Повреждение нейронов при диабетической нейропатии приводит к гиперактивации ионотропных рецепторов N-метил-D-аспартата. Активация NMDA-рецепторов вызывает развитие центральной сенситизации, которая в свою очередь приводит к появлению нейропатической боли. Прямое воздействие на указанные рецепторы связано с проявлением множества побочных эффектов, поэтому для безопасного лечения предпочтительно опосредованное воздействие, например, через блокирование натрий-кальциевого обменника (NCX). В этой связи применение селективного блокатора NCX KB-R7943 может быть перспективным при противоболевой терапии. Анализ ЭКГ не выявил негативного влияния KB-R7943 на состояние сердечно-сосудистой системы у контрольных и диабетических крыс. Тестирование в открытом поле показало, что после введения KB-R7943 поведение крыс (двигательная активность и признаки тревожности) не меняется. Проведен анализ уровня экспрессии гена потенциал-зависимого натриевого канала Nav1.7 (SCN9A), α2δ-1 субъединицы потенциал-зависимых кальциевых каналов Т-типа (CACNA2D1), Bax и Bcl-2, задействованных в патогенезе диабетической нейропатии, в тканях гиппокампа и гипоталамуса. Показано, что при введении KB-R7943 в гиппокампе у диабетических крыс экспрессия CACNA2D1 возрастала, а SCN9A — снижалась; у животных контрольной группы под влиянием препарата повышался уровень мРНК Nav1.7. Экспрессия Bax и Bcl-2 усиливалась в гиппокампе у контрольных животных после введения KB-R7943. У диабетических крыс терапия KB-R7943 приводила к снижению уровня мРНК Всl-2 в гипоталамусе и не влияла на уровень экспрессии Bах.