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A new water-soluble benzodiazepine derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast-onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL -001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL -001 was chosen as the optimal compound for studies of ED50, LD50, latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL -001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL -001 has a shorter period of induction despite a slightly longer sedative duration and recovery time. [ABSTRACT FROM AUTHOR]

We report the synthesis of novel, potentially hypnotic fluorine-substituted phenyl acetate derivatives. We describe the structure–activity relationship that led us to the promising derivative: ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-fluorophenyl) acetate ( 55 ). The unique pharmacological features of compound 55 are its relatively high affinity for the GABA A receptor, together with a unique affinity for the NMDA receptor, different to propanidid and AZD3043. In animal models, compound 55 showed stronger hypnotic potency and longer duration of LORR than propanidid and AZD3043, but also maintained a rapid recovery time to walking and behavioral recovery. In particular, compound 55 displayed reflex depression during infusion. [ABSTRACT FROM AUTHOR]

Background: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. Methodology/Principal Findings: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. Conclusions/Significance: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness. [ABSTRACT FROM AUTHOR]

• LPS-induced depression associates with increased CD38 levels in selected brain regions. • Inhibiting CD38 relieves depression-like behaviors via regulating neuroinflammation and synaptic function. • Inhibiting CD38 decreases excessive microglia activation via Sirt1-STAT3-NF-кB signaling pathway. • Neuronal activation in CA3 of hippocampus produces antidepressant effects. • The antidepressant effects of (R)-ketamine are related to decreased CD38 levels. CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development. [ABSTRACT FROM AUTHOR]

Compound (I) shows high affinity for dopamine D2 and D3, serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors with a low affinity for the H1 receptor. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and sigma-1 receptor (σ 1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure–activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1-(4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (K i σ 1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment. [Copyright &y& Elsevier]

Highlights: [•] EGb 761 treatment significantly reduced the infarct volume. [•] EGb 761 decreased ischemia-induced apoptosis in ipsilateral cortex and hippocampus. [•] Neurogenesis in the hippocampus was enhanced by EGb 761 treatment. [•] The colocalization of PSA-NCAM and BrdU was enhanced by EGb 761 treatment. [ABSTRACT FROM AUTHOR]

Thediscovery and synthesis of potential and novel antipsychoticcoumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1Aand 5-HT2Areceptor properties, are the focus of the present article. The most-promisingderivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possessesunique pharmacological features, including high affinity for dopamineD2and D3and serotonin 5-HT1Aand5-HT2Areceptors. Moreover, it possesses low affinity for5-HT2Cand H1receptors (to reduce the riskof obesity associated with chronic treatment) and hERG channels (toreduce the incidence of torsade des pointes). In animal models, compound 17minhibited apomorphine-induced climbing behavior, MK-801-inducedhyperactivity, and the conditioned avoidance response without observablecatalepsy at the highest dose tested. Further, fewer preclinical adverseevents were noted with 17mcompared with risperidonein assays that measured prolactin secretion and weight gain. Acceptablepharmacokinetic properties were also noted with 17m.Taken together, 17mmay constitute a novel class of drugsfor the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D 2 , K i = 0.5 ± 0.07 nM; 5-HT 1A , K i = 5.9 ± 0.8 nM; 5-HT 2A , K i = 0.3 ± 0.01 nM; 5-HT 6 , K i = 0.5 ± 0.04 nM) and combined with low affinities for the H 1 , 5-HT 2C , and adrenergic α 1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia. [ABSTRACT FROM AUTHOR]

The discovery of the robust antidepressant actions of ketamine is regarded as one of the greatest advancements in depression treatment in the past 60 years. Recent findings have provided strong evidence for the presence of bidirectional communication networks between the gastrointestinal tract and the brain in depression. Moreover, increasing evidence supports the antidepressant role of ketamine in regulating the gut microbiome and microbiota-derived molecules; however, the mechanisms underpinning such effects are still ambiguous. This review summarizes the current understanding of the anti-depressant mechanisms of ketamine and its metabolites regarding the bidirectional regulation by microbiota–gut–brain axis. We review the relationship between gut microbiota and the antidepressant mechanisms of ketamine, and discuss the role of stress response, brain-derived neurotrophic factor (BDNF)-mediated neurogenesis, anti-inflammatory effect and neurotransmitters. • Ketamine and its metabolites exert rapid-acting and sustained antidepressant effects. • Gut microbiota contributes to the pathogenesis of depression and the antidepressant actions of ketamine and its metabolites. • The relationship between gut microbiota and the antidepressant effects of ketamine and its metabolites is related to stress response, BDNF expression, neurogenesis, anti-inflammatory effect and neurotransmitters. [ABSTRACT FROM AUTHOR]

Anesthetic ketamine is a racemic mixture containing equal amount of (R)-ketamine and (S)-ketamine. Increasing preclinical data show that (R)-ketamine has a rapid-onset and sustained antidepressant without significant side effects. There are currently many studies on (R)-ketamine, however, the quantity and quality of these studies are unknown. Therefore, we conducted a bibliometric analysis of research on (R)-ketamine from January 2002 to December 2021. We obtained the publications on (R)-ketamine from the Web of Science database during the period. A variety of bibliographic elements were collected, including annual publications, authors, countries/regions, institutions, journals, and keywords. A total of 922 publications were included in this study. Professor Kenji Hashimoto of Chiba University in Japan was the most productively influential author in the field of (R)-ketamine and the authors from United States were the leader in this field. In addition, we found that the antidepressant effect of (R)-ketamine has been a hotspot in very recent years. This study provided a comprehensive analysis of research on (R)-ketamine and highlighted the growing interest in (R)-ketamine and its antidepressant effects. • A total of 922 publications on (R)-ketamine from January 2002 to December 2021 were analyzed. • Professor Kenji Hashimoto of Chiba University was the most productively influential author in the field of (R)-ketamine. • The antidepressant effect of (R)-ketamine has been a hotspot in recent years. [ABSTRACT FROM AUTHOR]

Thediscovery and synthesis of a new series of pyrimidines as potentsigma-1 receptor (σ1R) antagonists, associated withpharmacological antineuropathic pain activity, are the focus of thisarticle. The new compounds were evaluated in vitro in σ-1 andσ-2 receptor binding assays. The nature of the pyrimidine scaffoldwas crucial for activity, and a basic amine was shown to be necessaryaccording to the known pharmacophoric model. The most promising derivativewas 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine(137), which exhibited a high binding affinity to σ1R receptor (Kiσ1= 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivotests, compound 137exerted dose-dependent antinociceptiveeffects in mice formalin model and rats CCI models of neuropathicpain. In addition, no motor impairments were found in rotarod tests;acceptable pharmacokinetic properties were also noted. These datasuggest compound 137may constitute a novel class ofdrugs for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Abstract: A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a–5d and 8a–8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (K i =17nM) and 5-HT2A (K i =0.71nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice. [Copyright &y& Elsevier]

Abstract: In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors, together with a low affinity for H1 receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine. [Copyright &y& Elsevier]

Objective. This study is designed to observe the urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) levels in patients with lupus nephritis (LN) and to identify new biomarker of lupus nephritis activity. Methods. Study subjects were 46 cases of patients with LN (including 34 of active cases) who underwent routine renal biopsy. Activity and chronicity indexes of LN were assessed using pathological criteria proposed by Hill et al. in 2000. Urinary TWEAK (uTWEAK) level and Monocyte chemoattractant protein-1 (MCP-1) level were detected by ELISA. Results. Urinary TWEAK level was significantly higher in active LN group than in non-active LN group. Correlation analysis showed that urinary TWEAK levels were significantly correlated with activity index (r = 0.825, P < 0.01), glomerular activity index (r = 0.754, P < 0.01), and tubulointerstitial qualitative activity index (r = 0.751, P < 0.01), while not significant correlated with chronicity Index (P > 0.05). The association between urinary TWEAK levels and urinary MCP-1 levels were significant in active LN group (r = 0.809,P < 0.01) but not significant in non-active LN group (P > 0.05). Conclusions. uWEAK levels were correlated with all active indexes of LN, suggesting its potential role as novel biomarker of active lupus nephritis. [ABSTRACT FROM AUTHOR]

Objective. This study is designed to observe the urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) levels in patients with lupus nephritis (LN) and to identify new biomarker of lupus nephritis activity. Methods. Study subjects were 46 cases of patients with LN (including 34 of active cases) who underwent routine renal biopsy. Activity and chronicity indexes of LN were assessed using pathological criteria proposed by Hill et al. in 2000. Urinary TWEAK (uTWEAK) level and Monocyte chemoattractant protein-1 (MCP-1) level were detected by ELISA. Results. Urinary TWEAK level was significantly higher in active LN group than in non-active LN group. Correlation analysis showed that urinary TWEAK levels were significantly correlated with activity index (r = 0.825, P < 0.01), glomerular activity index (r = 0.754, P < 0.01), and tubulointerstitial qualitative activity index (r = 0.751, P < 0.01), while not significant correlated with chronicity Index (P > 0.05). The association between urinary TWEAK levels and urinary MCP-1 levels were significant in active LN group (r = 0.809,P < 0.01) but not significant in non-active LN group (P > 0.05). Conclusions. uWEAK levels were correlated with all active indexes of LN, suggesting its potential role as novel biomarker of active lupus nephritis. [ABSTRACT FROM AUTHOR]