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

Abstract

Purpose 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.

Drug transport by red blood cells

“…One parameter which is still undescribed is the B/P ratio. Manchester et al (2022 ) used gas chromatography tandem to mass spectrometry to determine the blood-to-plasma ratio for the following benzodiazepines: deschloroetizolam, diclazepam, etizolam, meclonazepam, phenazepam, and pyrazolam ( Manchester et al, 2022 ). The results reported various ranges of blood-to-plasma ratios, some of which significantly differ from those found in the literature.…”