Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances in order to interpret and predict their effects upon humans. Experimental log D7.4, pKa and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3‐hydroxyphenazepam, 4’‐chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam) and compared with values generated by various software packages (ACD/I‐lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I‐LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa. Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future ‘training’ of predictive models for these new psychoactive substances

The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines

The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these ‘new’ benzodiazepines. In order to further understand the pharmacology of ‘new’ benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABAA receptors. The QSAR model returned an R2 value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R2 value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future

The Physicochemical and Pharmacokinetic Properties of Benzodiazepines Appearing as New Psychoactive Substances

Benzodiazepines are a class of compounds that were initially developed for medicinal purposes. Multiple benzodiazepines have appeared as `new psychoactive substances' on the illicit drug market and have never been developed for medicinal use. Very little pharmacokinetic data exists regarding them. This information is valuable as it allows the prediction and interpretation of their effects in humans and aids with forensic and toxicological work. In this work the lipophilicity (log D7.4), the pKa and the plasma protein binding were determined for benzodiazepines appearing as new psychoactive substances and these were compared to theoretical values from software packages. ACD/I-LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa. None of the software packages were able to predict parameters to a su_cient degree of accuracy and in vitro data is currently preferable. An improved relationship to calculate the volume of distribution at steady state (Vdss) by using the Oie-Tozer equation, the log D7.4, the pKa and the plasma protein binding of benzodiazepines was developed. The Vdss of benzodiazepines could be predicted to within a 1.11-fold accuracy. The blood to plasma concentration ratios of six benzodiazepines appearing as new psychoactive substances were determined. Despite the small dataset a large variation in ratios was observed, from 0.57 for phenazepam to 1.18 for pyrazolam, highlighting the need for accurate pharmacokinetic data. The metabolic characterisation of illicit compounds is an important aid in toxicological interpretations. This is commonly performed in vitro using human hepatocellular carcinoma cell lines and the choice of cell line is crucial in order to obtain reliable results. The C3A and HepaRG cell lines were characterised with respect to six major phase I metabolic enzymes. HepaRG was shown to have a greater expression of these enzymes and thus have a superior utility in a metabolic study. The metabolism of 12 benzodiazepines appearing as new psychoactive substances was investigated with the HepaRG cell line. Some of the benzodiazepines were observed to have different metabolic pathways to those previously reported. This again highlights the need for accurate experimental data in order to assess the pharmacokinetics of new psychoactive substances

From Classroom to Clinic: Bridging the Gap in Nursing Anatomy and Physiology Education

YesSince the 1980 s, changes in nursing education have inadvertently led to diminishing anatomy and physiology content in curricula (Taylor et al., 2015). The need for nurses to have a thorough grounding in these subjects is undisputed; however, the pedagogical principles for anatomy and physiology education have been under scrutiny (Perkins, 2019). Anatomy and physiology are typically incorporated as part of bioscience, which also encompasses genetics, microbiology, pharmacology, and pathophysiology (Horiuchi-Hirose et al., 2023). Registered nurses and nursing students often express anxiety about studying bioscience and its perceived difficulty, largely due to difficulties in applying theory to practice (Craft et al., 2013, Craft et al., 2017, Meedya et al., 2019). Despite this, there remains a recognition that bioscience knowledge is important for effective nursing practice (Danielson and Berntsson, 2007, Horiuchi-Hirose et al., 2023).The full-text of this article will be released for public view at the end of the publisher embargo on 15 Dec 2024

Designer benzodiazepines gidazepam and desalkygidazepam (bromonordiazepam): What do we know?

YesDesigner benzodiazepines are one of the primary new psychoactive substances (NPS) threats around the world, being found in large numbers in post-mortem, driving under the influence of drugs (DUID) and drug facilitated sexual assault (DFSA) cases. Even though when compared to many other NPS types, such as opioids and cathinones, there are relatively few designer benzodiazepines being monitored. Recently a new NPS benzodiazepine has been reported in Europe, the USA and Canada, desalkygidazepam, also known as bromonordiazepam. This substance is a metabolite of the pro-drug gidazepam, a drug licenced for use in Ukraine and Russia under the name Gidazepam IC®. In the paper we review what is currently known about the use, pharmacology and analytical detection of gidazepam, its metabolite desalkygidazepam, and their other possible metabolites.The full-text of this article will be released for public view at the end of the publisher embargo on 25 Jan 2024

Designer benzodiazepines gidazepam and desalkygidazepam (bromonordiazepam): what do we know?

Designer benzodiazepines are one of the primary new psychoactive substances (NPS) threats around the world, being found in large numbers in post-mortem, driving under the influence of drugs (DUID) and drug facilitated sexual assault (DFSA) cases. Even though when compared to many other NPS types, such as opioids and cathinones, there are relatively few designer benzodiazepines being monitored. Recently a new NPS benzodiazepine has been reported in Europe, the USA and Canada, desalkygidazepam, also known as bromonordiazepam. This substance is a metabolite of the pro-drug gidazepam, a drug licenced for use in Ukraine and Russia under the name Gidazepam IC®. In the paper we review what is currently known about the use, pharmacology and analytical detection of gidazepam, its metabolite desalkygidazepam, and their other possible metabolites

The blood-to-plasma ratio and predicted GABAA-binding affinity of designer benzodiazepines

YesPurpose: The number of benzodiazepines appearing as new psychoactive substances (NPS) is continually increasing. Information about the pharmacological parameters of these compounds is required to fully understand their potential effects and harms. One parameter that has yet to be described is the blood-to-plasma ratio. Knowledge of the pharmacodynamics of designer benzodiazepines is also important, and the use of quantitative structure–activity relationship (QSAR) modelling provides a fast and inexpensive method of predicting binding affinity to the GABAA receptor. Methods: In this work, the blood-to-plasma ratios for six designer benzodiazepines (deschloroetizolam, diclazepam, etizolam, meclonazepam, phenazepam, and pyrazolam) were determined. A previously developed QSAR model was used to predict the binding affinity of nine designer benzodiazepines that have recently appeared. Results: Blood-to-plasma values ranged from 0.57 for phenazepam to 1.18 to pyrazolam. Four designer benzodiazepines appearing since 2017 (fluclotizolam, difludiazepam, flualprazolam, and clobromazolam) had predicted binding affinities to the GABAA receptor that were greater than previously predicted binding affinities for other designer benzodiazepines. Conclusions: This work highlights the diverse nature of the designer benzodiazepines and adds to our understanding of their pharmacology. The greater predicted binding affinities are a potential indication of the increasing potency of designer benzodiazepines appearing on the illicit drugs market.Engineering and Physical Sciences Research Council