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

Manchester, Kieran R.
; 
Waters, L.
; 
Haider, S.
; 
Maskell, P.D.
Publication Date
2022-03
End of Embargo
Supervisor
Keywords
Research Development Fund Publication Prize Award, QSAR, Designer benzodiazepines, New psychoactive substances, Blood-to-plasma ratio, GABAA receptor
Rights
© 2022 The Author(s). This is an Open Access article distributed under the Creative Commons CC-BY license(https://creativecommons.org/licenses/by/4.0/)
cb
Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2022-02-16
Institution
Department
Awarded
Embargo end date
Collections
Health Studies Publications
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Manchester_et_al_Forensic_Toxicology
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Abstract
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.
URI
http://hdl.handle.net/10454/18785
Version
Published version
Citation
Manchester KR, Waters L, Haider S et al (2022) The blood-to-plasma ratio and predicted GABAA-binding affinity of designer benzodiazepines. Forensic Toxicology. 40: 349-356.
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Link to Version of Record
https://doi.org/10.1007/s11419-022-00616-y
Type
Article
Qualification name
Notes
Research Development Fund Publication Prize Award winner, Feb 2022.