ACS Chemical Neuroscience最新文献

Alzheimer’s disease (AD) is the leading cause of dementia, characterized by progressive oxidative stress, neuroinflammation, and cognitive decline. Current pharmacological therapies are largely symptomatic, underscoring the need for new disease-modifying strategies. Drug repurposing provides an efficient approach to exploiting clinically approved compounds with established safety. Hence, in the current study, we investigated the neuroprotective potential of cefotaxime (CTX), a third-generation cephalosporin antibiotic, in an intracerebroventricular streptozotocin (ICV-STZ) rat model of AD. Adult male Sprague–Dawley rats were administered CTX (100–300 mg/kg, intraperitoneal, 28 days) and compared with donepezil (5 mg/kg). Behavioral performance was assessed using the Morris water maze, Y-maze, elevated plus maze, and open field tests. Biochemical assays (oxidative stress markers), histopathology, immunohistochemistry, ELISA, and RT-PCR were employed to examine molecular and cellular changes. CTX significantly ameliorated STZ-induced cognitive deficit, anxiety-like behaviors, oxidative stress, and neuroinflammation. While CTX reduced mRNA expression of β-amyloid and tau, it did not lower their protein levels as determined by ELISA, suggesting selective modulation at transcriptional rather than post-translational levels. Together, these findings suggest a potential role for CTX as a promising repurposed candidate for alleviating AD-related neurobehavioral deficits through the modulation of oxidative stress and inflammatory pathways.

General anesthetics like propofol are widely used, but their molecular mechanisms remain poorly understood, limiting the rational design of novel anesthetics or antagonists to enhance safety. We evaluated nine propofol derivatives for their ability to immobilize, or modulate propofol-induced immobilization, in larval zebrafish, using spontaneous and elicited movement as distinct endpoints. We hypothesized that compounds unable to act as hydrogen-bond donors would antagonize immobilization─evidenced by rightward EC₅₀ shifts─while hydrogen-bond-capable derivatives would retain immobilizing effects. Results confirmed that nondonor analogues antagonized propofol’s effects, whereas donor molecules had sedative activity, and a hydrocarbon control did not shift the EC₅₀ curve. Quantum-mechanical calculations of hydrogen-bond acidity were correlated to behavioral outcomes, supporting their predictive potential. Notably, a tertiary amine analogue (PEARL 6, N,N-dimethyl-2,6-diisopropylaniline) antagonized most strongly (25.6-fold increase in propofol’s EC₅₀ for spontaneous movement and a 1.86-fold increase for elicited movement) without causing excitation when administered alone. These findings identify structural features that distinguish sedative from antagonistic activity and provide characterization of a key feature of propofol derivatives.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that can lead to brain cell death and brain atrophy, manifested as memory loss, cognitive decline, and behavioral abnormalities. Its mechanism is complex, and there is currently no effective treatment method. The search for new therapies and natural drug candidates has become the focus of research. In recent years, marine-derived strains of Aspergillus terreus have become an important research direction for treating AD due to the unique structure and biological activity of their secondary metabolites. In this study, we investigated the potential of two alkaloids from Aspergillus terreus C23–3 in the treatment of AD through bioinformatics analysis and experimental validation. Bioinformatics analyses showed that the two alkaloids may act by modulating key targets associated with AD, especially alkaloid 2, which may exert significant therapeutic effects on AD by inhibiting glycogen synthase kinase-3β (GSK-3β) activity and reducing the level of hyperphosphorylation of Tau proteins. Molecular docking experiments showed that alkaloids 1 and 2 formed stable complexes with GSK-3β with a high affinity. Cellular experiments showed that alkaloids 1 and 2 could effectively inhibit apoptosis and injury in HT-22 cells. Further studies showed that alkaloid 2 reduced the phosphorylation level of Tau protein and attenuated oxidative-stress-induced neurological injury by inhibiting GSK-3β and its related pathways. These results suggest that alkaloid 2 has significant potential for AD therapy.

A new assembly of furano-fused azepinone derivatives was carried out in two steps, i.e., 3 + 2 cycloaddition followed by hydroxylammonium-O-sulfonic acid (HOSA)-assisted Beckmann rearrangement in aqueous conditions. This methodology uses a readily available starting synthon, dimedone, to synthesize five- and six-membered condensed furano-azepinone derivatives 5(a-n), and their structures were validated by spectral techniques. In vitro antiacetylcholinesterase (AchE) activity revealed that compound 5n (IC₅₀= 2.38 ± 0.02 nM) showed higher inhibitory activity than reference drugs galantamine (IC₅₀ = 2.84 ± 0.01 nM). Later, cytotoxicity studies of the synthesized compounds were conducted on SHSY5Y cell lines, indicating the concentration-dependent inhibition, i.e., the highest cell viability at 25 μM, whereas the lowest viability at 400 μM. Further intracellular ROS measurements indicate that 5n exhibits superior ROS-scavenging capabilities in fluorescence-based assays. Molecular docking and density functional theory (DFT) analyses were applied to further validate the binding interactions of the compounds with the AchE active site. The combined experimental and computational investigation revealed that 5n exhibits significant anti-AchE activity and warrants further exploration for its medicinal utility in Alzheimer’s disease and related challenges. The design, synthesis, and AchE inhibitory properties of the synthesized furano-azepinone derivatives were patented under Indian patent number 202511048244.

Chromone-based small organic molecules are designed and synthesized as putative multipotent ligands to intervene in several interlinked pathological pathways of Alzheimer’s disease. The synthesized compounds were evaluated as acetylcholinesterase, monoamine oxidase, and amyloid β aggregation inhibitors using biochemical assays. Most of the compounds were found to inhibit the enzymes in a lower micromolar concentration range. In the series, two compounds, i.e., NSS-16 and NSS-18, displayed a balanced activity profile with the IC₅₀ values of 1.77 and 1.53 μM against AChE and 2.06 and 1.51 μM against MAO-B. NSS-16 and NSS-18 showed moderate inhibitory activity against the self-induced Aβ aggregation with inhibition percentages of 17.8 and 24.0%, respectively. These compounds also showed potent antioxidant activity and formed metal chelates. In addition, the compounds were tested against SH-SY5Y neuronal cells and found to be neuroprotective and noncytotoxic. Moreover, the compounds inhibited reactive oxygen species (ROS) production up to 70% and exhibited a mixed type of inhibition in enzyme kinetic studies of AChE. These chromone derivatives showed a strong fluorescence intensity with a quantum yield of 30–50% and can be utilized in various biological studies including in vitro and in vivo assessments. Computational studies showed that the lead compounds fit well in the active cavity of enzymes and displayed thermodynamic stability for a time interval of 100 ns. Thus, these compounds displayed a multipotent activity profile and have the potential to be developed as potential therapeutics for AD.

Intractable forms of recurrent seizures occur in approximately 30% of epileptic patients. Therefore, development of new antiseizure therapies is of special urgency. Improvement of inhibition in epileptic circuitries is currently believed to be a promising strategy for treating epilepsy. This is mainly due to the following observations. A deficit of GABAergic transmission has been documented in epileptic patients and various animal models of epilepsy, and a pharmacological increase of synaptic GABA produces an anticonvulsive effect. Genetic intervention of GABAergic interneurons offers an opportunity to selectively modulate their activity. In recent years, the efficiency of on-demand control of seizures via opto- or chemogenetic modulation of inhibitory networks has been confirmed in various in vivo and acute brain slice models of epilepsy. It was found that suppression of seizures can be achieved by opto- or chemogenetic modulation of local and distant inhibitory neurons, and recruitment of a mixed population of GABAergic interneurons results in more potent seizure suppression than recruitment of their single subclasses. The major advantage of this strategy is that the activity of neuronal networks outside the epileptic zone and during interseizure intervals remains intact, thus preserving normal brain function. However, the dual role of inhibitory networks in ictogenesis may compromise the future development of this approach. In this review, we focus on recent advances in developing therapies for epilepsy treatment by genetic intervention of GABAergic INs, caveats to consider when manipulating the function of GABAergic INs using genetic tools, and considerations to overcome these caveats.

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, shows promise in treating depression and post-traumatic stress disorder (PTSD), resulting in breakthrough status. However, concerns regarding MDMA’s abuse potential and cytotoxicity have sparked interest in developing safer analogues with similar therapeutic benefits. This study investigated the pharmacological properties of MDMA analogues in which the 1,3-benzodioxole group is replaced by a 1,3-benzoxathiole, termed SDA and SDMA, compared to MDA and MDMA through in silico, in vitro, and in vivo assays. In vitro experiments using human embryonic kidney (HEK293) cells examined the interactions with monoamine transporters. SDA and SDMA showed similar profiles to MDMA at the serotonin transporter (SERT), while both inhibited dopamine (DAT) and norepinephrine (NET) transporters more potently, in line with in silico molecular docking fitness scores of binding. SDA and SDMA also showed increased potency in evoking efflux through SERT and DAT acting as partial releasers. SDA and SDMA exhibited a similar interaction profile with 5-HT₂ receptors compared with their respective analogues. Metabolism studies revealed faster clearance rates for SDA and SDMA, in contrast to MDA and MDMA, which exhibited only weak degradation. In contrast to MDMA’s rewarding effects, SDMA did not induce significant effects in mice, while SDA only produced a significant preference for the drug-paired compartment at the lowest dose tested. Moreover, while SDMA shares similar locomotor and hyperthermic profiles as MDMA in mice, SDA induced increased hyperlocomotion and more sustained hyperthermia. In conclusion, these findings suggest that SDMA, with enhanced metabolic profiles and reduced abuse potential, is a promising candidate for further studies.

Psychostimulant use disorder (PSUD) remains an unmet medical need, with no FDA-approved pharmacotherapies currently available. The dopamine D3 receptor (D₃R), due to its selective expression in mesolimbic reward circuits, has emerged as a compelling target for PSUD intervention. We used cariprazine (1a), a D₃R-preferring antipsychotic that reduces cocaine-related behaviors in preclinical models, as a scaffold for the synthesis of a library of novel derivatives. We employed BRET-based assays to functionally characterize their effects on G protein and β-arrestin2 signaling at D₃R. Structure–function relationship analyses revealed that modifications to the phenylpiperazine moiety of cariprazine are the key determinants of D₃R efficacy, potentially through diverse interactions with transmembrane segment 5. Moreover, certain substitutions to this aromatic primary pharmacophore appear to confer D₃R/D₂R functional divergence. These findings offer key mechanistic insights and inform the rational design of next-generation bitopic ligands with optimized signaling properties for the treatment of PSUD and related disorders.

Visualizing signaling systems in the brain with high spatial resolution is critical to understanding brain function and to develop therapeutics. Especially, enzymes are often regulated on the post-translational level, resulting in a disconnect between protein levels and activity. Conventional antibody-based methods have limitations, including potential cross-reactivity and the inability of antibodies to discriminate between active and inactive enzyme states. Monoacylglycerol lipase (MAGL), an enzyme degrading the neuroprotective endocannabinoid 2-arachidonoylglycerol, is the target of inhibitors currently in clinical trials for the treatment of several neurological disorders. To support translational and (pre)clinical studies and fully realize the therapeutic opportunities of MAGL inhibitors, it is essential to map the spatial distribution of MAGL activity throughout the brain in both health and disease. Here, we introduce selective fluorescent activity-based probes for MAGL enabling direct visualization of its enzymatic activity in lysates, cultured cells, and tissue sections. We show that oxidative stress, which inactivates MAGL through the oxidation of regulatory cysteines, reduces probe labeling, thereby validating the probes activity-dependence. Extending this approach, we developed an activity-based histology protocol to visualize MAGL activity in fresh-frozen mouse and human brain tissues. This approach revealed robust MAGL activity in astrocytes and presynaptic terminals within the mouse hippocampus and further allows detection of MAGL activity in the human cerebral cortex. Collectively, these findings establish selective activity-based probes as powerful tools mapping MAGL activity with high spatial resolution across mammalian brain tissue.

We recently disclosed VU0467319, a muscarinic acetylcholine receptor subtype 1 (M₁) Positive Allosteric Modulator (PAM) clinical candidate that had successfully completed a Phase I Single Ascending Dose (SAD) clinical trial, but the identification of an inactive metabolite constituting a major portion of the total plasma AUC detracted from the molecules’ pharmacokinetic profile and contributed to clinical development discontinuation. Attempts to block metabolism with the incorporation of deuterium atoms proved successful in vitro and in vivo at low exposures; however, in high-dose nonclinical toxicology studies, the degree of oxidative metabolism and metabolite accumulation was comparable to that of the proteo-congener. Here, we describe a second-generation back-up effort based on the VU0467319 scaffold to discover VU6052254. Strategic placement of a tertiary hydroxyl moiety afforded VU6052254, a potent M₁ PAM (EC₅₀ = 59 nM, 79% ACh max), with high CNS exposure (rat K_p = 1.07; K_p,uu = 1.27; P-gp ER = 1.97, P_app = 23 × 10^–6 cm/s), reduced metabolism across species, excellent pharmacodynamic responses (MED in rat NOR = 1 mg/kg PO; MED in rat CFC = 0.3 mg/kg PO), excellent multispecies PK (Cl_ps < 10 mL/min/kg, %F > 65), and favorable human PK and dose projections. Based on these beneficial attributes, VU6052254 was nominated for further nonclinical development. However, possible CYP₄₅₀ induction liability as well as uncertain projected margins for human efficacy at those systemic concentrations where dose/exposure-related clinical and anatomic pathology kidney findings were observed in a 14-day exploratory toxicity study in male rats, precluded further development.