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SummaryPurpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.

Type-A γ-aminobutyric (GABA ) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA receptor modulators.

Remimazolam (Anerem ® in Japan; ByFavo™ in the USA; Aptimyda™ in the EU) is an ultra-short-acting intravenous (IV) benzodiazepine sedative/anesthetic being developed by PAION AG in conjunction with a number of commercial partners for use in anesthesia and procedural sedation. Remimazolam was approved on 23 January 2020 in Japan for use in general anesthesia in adult patients. Remimazolam is also undergoing regulatory assessment in South Korea for this indication and for use in procedural sedation in the USA, the EU and China. This article summarises the major milestones in the development of remimazolam for this first approval for the induction and maintenance of general anaesthesia, and its potential upcoming approvals in general anaesthesia and procedural sedation.

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment. Benzodiazepines, used to treat anxiety and sleep disorders, may cause cognitive impairment. Shi et al. demonstrate that this is caused by interaction with the mitochondrial protein TSPO, which drives microglia to excessively remove synapses.

Silylation is a widely used derivatization technique for the gas chromatographic analysis of benzodiazepines, a class of psychoactive drugs commonly encountered in forensic and biological samples. This study investigated the optimal experimental conditions for the silylation of benzodiazepines using N,O-bis(trimethylsilyl)trifluoroacetamide containing 1% trimethylchlorosilane (BSTFA + 1% TMCS), a widely employed silylating agent. Ten structurally different benzodiazepines, including variations within the classic 1,4-benzodiazepine core and triazolo ring derivatives, were selected to address the effect of structural diversity on silylation. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used to optimize the silylation of benzodiazepines by means of GC-MS analysis. PCA identified key experimental factors influencing silylation efficiency and distinct response patterns of different benzodiazepines. HCA further categorized the benzodiazepines based on their silylation behavior, highlighting the need for tailored derivatization strategies. The results indicated that the BSTFA + 1% TMCS concentration and solvent volume were pivotal for achieving high silylation efficiency, whereas the temperature, reaction time, and catalyst were less critical. The optimized method was successfully applied to 30 real forensic samples, demonstrating its efficacy in detecting and identifying various benzodiazepines, including designer drugs like etizolam. This study provides a foundation for improving drug detection methodologies in forensic toxicology and provides useful insights into the dynamics of benzodiazepine silylation and the use of individualized analysis parameters.

Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases. Using cryo-electron microscopy, the authors reveal the mechanism by which perampanel-like molecules inhibit AMPA receptors. They show that the inhibitors decouple the ligand-binding domain from the ion channel after neurotransmitter binding and outcompete positive modulators.

This study aims to assess the potential bioactivity of newly designed benzodiazepine-1,2,3-triazole derivatives using in-silico methodologies, with a primary focus on elucidating their inhibitory interactions with the butyrylcholinesterase (BuChE) enzyme, which is implicated in Alzheimer’s disease. We employed multiple linear regression (MLR) methods to conduct a quantitative structure-activity relationship (QSAR) analysis on a collection of 31 benzodiazepine-1,2,3-triazole derivatives, with the goal of investigating, assessing, and predicting their activities, as well as designing novel compounds. This approach yielded highly accurate results, with coefficients of determination (R²) of 0.77 and 0.81 for the training and test datasets, respectively. Additionally, the optimized compounds were subjected to an Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis, demonstrating their potential as non-hepatotoxic agents with enhanced absorption and blood-brain barrier permeability. To further validate these findings, the most favorable docking conformations were analyzed using molecular dynamics (MD) simulations with GROMACS software, predicting the stability of the formed complexes. These simulations underscored the critical role of hydrogen bonds in stabilizing the compounds at the BuChE receptor binding site. The results hold great promise for the development of innovative benzodiazepine-1,2,3-triazole derivatives as effective BuChE inhibitors, potentially leading to therapeutic interventions for Alzheimer’s disease.

Benzodiazepines are widely recognized for their therapeutic benefits in the treatment of anxiety and insomnia. However, in the pursuit of innovative anticancer agents, they have gained attention as a possible pharmacophore. One of those promising anticancer benzodiazepines is 3b which was demonstrated to exert good antiproliferative effects. To investigate the anticancer effect of 3b , in silico prediction of the possible targets were performed. Then, the predicted targets were investigated through in vitro study. Furthermore, 3b was evaluated for its effects on cell cycle suppression and induction of apoptosis. Molecular docking was used to study the possible types of interactions while molecular dynamics simulations were conducted to estimate the protein–ligand complex’s stability and dynamic behavior. Results demonstrated that 3b is a potent dual inhibitor of HER2 and HDAC1 with IC 50 values of 0.023 and 0.041 nM, respectively. Moreover, 3b was found to suppress cell cycle progression in G2/M phase and induce early and late apoptosis in HepG2 cancer cells. Further analysis of apoptotic markers revealed an induction of Caspase 3 and BAX proapoptotic proteins along with a suppression of the antiapoptotic protein (Bcl-2). Molecular docking of 3b into the active site of HER2 and HDAC1 displayed significant types of interactions with active sites of these target proteins while molecular dynamics simulations demonstrated the overall structural stability of HER2 and HDAC1 is maintained or even enhanced upon ligand binding. In conclusion, 3b is a powerful anticancer agent that exerts its effects by inhibiting HDAC1 and HER2, resulting in cell cycle arrest and cancer cell death through apoptosis. Nonetheless, additional investigations are needed to explore its mechanisms and therapeutic efficacy in more detail.