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Designer Benzodiazepines
Published in Ornella Corazza, Andres Roman-Urrestarazu, Handbook of Novel Psychoactive Substances, 2018
Peter D. Maskell, Nathan E. Wilson
Apart from recreational use, benzodiazepines are also commonly co-ingested by other groups of drug users, particularly high-risk opioid users1 with an estimated 38–75% of high-risk opioid users abusing benzodiazepines (Heikman, Muhonen, & Ojanperä, 2017; Jones, Mogali, & Comer, 2012). The combination of benzodiazepines with opioids potentiates the clinical features seen, including extreme sleepiness and risk of overdose (Park, Saitz, Ganoczy, Ilgen, & Bohnert, 2015). This concomitant abuse of benzodiazepines is of particular concern, as this increases the risk of non-fatal and fatal overdose, particularly due to respiratory depression (White & Irvine, 1999). Around the world, Benzodiazepines were identified in between 40% and 80% of opioid-related deaths, showing the increased risk of abuse of opioids and benzodiazepines (EMCDDA n.d.). For licenced benzodiazepines, it has been estimated from a study in the USA that in unintentional deaths involving benzodiazepines, only 46% of the users had a valid prescription (Toblin, Paulozzi, Logan, Hall, & Kaplan, 2010). Opioid users are abusing NPS benzodiazepines as well as licenced benzodiazepines; for example, in data from Scotland in 2016, etizolam, diclazepam, and phenazepam were detected in opioid deaths (Anon, 2017), showing that clinicians need to be aware of other drugs in any potential benzodiazepine overdose. The added complexity is that high-risk opioid users tend to use supra-therapeutic or ‘mega doses’ of benzodiazepines significantly above those prescribed. Between 40 and 150 mg of oral/intravenous temazepam and/or diazepam concentrations have been reported (Jones et al., 2012; Stitzer, Griffiths, McLellan, Grabowski, & Hawthorne, 1981; Robertson & Ronald, 1992). There is a lack of information on the effects of these high doses on pharmacokinetic and pharmacodynamic variables, particularly in overdose. In the treatment and determination of NPS benzodiazepine abuse, it can be important to determine that NPS benzodiazepines have actually been taken.
Designer benzodiazepines versus prescription benzodiazepines: can structural relation predict the next step?
Published in Critical Reviews in Toxicology, 2021
Raneem E. Moustafa, Fuad Tarbah, Huda Sulaiman Saeed, Suleiman I. Sharif
Benzodiazepine designer drugs are one of the substances that are fast-growing in the market and impose a challenge to toxicologists, clinicians and researchers. The close structural relationship between benzodiazepines may provide some information about the behavior of the unknown compounds but they are never proof until the unknown is studied up close. Benzodiazepines can target different subunits in the brain with multiple isoforms, which explains the variation observed in their activity and the extent of efficacy. Hence, relating benzodiazepines to each other may predict some, but not all, the knowledge needed. Most of the literature searched involving the active metabolites, nifoxipam and fonazepam depended on the information provided of flunitrazepam expecting them to be of the same pharmacokinetics and pharmacodynamics although some differences were found when studied. Interestingly, diazepam shared some characteristics with diclazepam. Nevertheless, other characteristics are yet to be determined like the relative strength of diclazepam compared to that of diazepam. On the other hand, diclazepam’s isomer, 4-chlorodiazepam, showed effects that are totally distinct from any other typical benzodiazepine including diazepam, such as anxiogenic and convulsive effects at high doses. This opened our eyes to a designer drug that may become an actual drug candidate.
Designer benzodiazepines: an update
Published in Expert Review of Clinical Pharmacology, 2023
Xiao Yu, H Karl Greenblatt, David J Greenblatt
The older and newer data sources are largely coalescent. It is evident that electronegative substitutions at the R7 and R2’ positions enhance receptor affinity [41,42]. Candidate substitutions of this type include -F, -Cl, -Br, -I, and -NO2. More electronegativity confers greater receptor affinity. Diclazepam is diazepam with -Cl added at R2’. Flubromazepam is diazepam with -Br at R7, and -F at R2’. Alkyl or hydroxy substitutions at R1 have a small effect on receptor affinity. Methylclonazepam is clonazepam with an R1 methyl substitution, while meclonazepam is clonazepam with an R3 methyl substitution. Similar substitution logic is applicable to generation of DBs from other benzodiazepine subclasses [6,7].