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Interaction of the benzodiazepines with the GABAA receptor
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
There is more evidence to suggest that triazolobenzodiazepines such as triazolam and alprazolam may have unusually high intrinsic activity. For example, using recombinant GABAAreceptors expressed in human embryonic kidney cells, triazolam has been shown to yield significantly larger potentiations of GABA-evoked currents than diazepam or clonazepam (Ducic et al, 1993). On the other hand, using chloride flux assays on cortical synaptosomes (Facklam et al, 1992a) or electrophysiological recordings in hippocampal neurons (Kemp et al, 1987) no difference in maximal potentiating effects between diazepam and triazolam was found. The discrepancy may be due to receptor subtypes as the maximum degree of potentiation, by a given benzodiazepine, can vary considerably between them and small differences in efficacy would be difficult to observe on responses measured in mixed populations of receptor subtype. Nevertheless, using ex vivo binding studies, Facklam et al (1992b) did notice that the receptor occupancy required to produce a given behavioural effect in a number of paradigms was often lower for triazolam than for diazepam. If triazolobenzodiazepines do indeed have higher intrinsic activity than classical 2-keto benzodiazepines, this may in part account for their powerful psychotropic effects and their perceived greater potential to produce withdrawal and dependence phenomena than classical compounds.
Pharmacokinetic-Pharmacodynamic Modeling in Drug Development: Comments and Applications
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Joseph C. Fleishaker, James J. Ferry
These studies, which include but are not limited to the majority of clinical pharmacokinetic studies conducted during drug development, may be viewed by some as completing requirements for drug registration or “completing the package”.15 A listing of these studies, which have been recently summarized,11,15 is contained in Table 3. These studies are also referred to as “labeling trials”. If they are to contribute in a meaningful way to package insert labeling of the compound, they should answer one of the two central questions “right drug” or “proper dosing”. The following discussion illustrates how pharmacokinetic-pharmacodynamic modeling addresses these issues in the context of labeling studies. The example presented is a case study using pharmacokinetic/pharmacodynamic studies performed to support the development of adinazolam (Figure 3), a triazolobenzodiazepine which possesses anxiolytic and antidepressant activity and is under development for treatment of generalized anxiety and panic disorders.16–20
Anxiolytics: Predicting Response/Maximizing Efficacy
Published in Mark S. Gold, R. Bruce Lydiard, John S. Carman, Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
The spontaneous anxiety attacks which occur in panic disorder and agoraphobia with panic attacks do not in general respond to benzodiazepines.217 An exception to this statement may be the triazolobenzodiazepine alprazolam. Sheehan et al. have reported high doses of alprazolam to have acute antipanic effects.218 Whether the failure of other benzodiazepines to block panic is because they haven’t been used in high enough doses, or whether the triazolo ring structure of alprazolam gives it new properties related to another receptor remains to be established.
Designer benzodiazepines: an update
Published in Expert Review of Clinical Pharmacology, 2023
Xiao Yu, H Karl Greenblatt, David J Greenblatt
At least six subclasses of DBs can be distinguished based on structural framework, and similarity to existing medically used benzodiazepines (Figure 1) [3–12]: 1,4-BenzodiazepinesTriazolobenzodiazepinesThienotriazolodiazepines (also termed thienodiazepines)1,5-Benzodiazepines2,3-BenzodiazepinesOxazolobenzodiazepines
Bioavailability and pharmacokinetic profile of balovaptan, a selective, brain-penetrant vasopressin 1a receptor antagonist, in healthy volunteers
Published in Expert Opinion on Investigational Drugs, 2021
Michael Derks, Sian Lennon-Chrimes, Andreas Guenther, Lisa Squassante, Christoph Wandel, Piotr Szczesny, Axel Paehler, Heidemarie Kletzl
Balovaptan is a triazolobenzodiazepine V1a receptor antagonist derived by scaffold-hopping from RG7713 and two other prototypes, and optimized to display high potency and selectivity, minimal P-glycoprotein-mediated brain efflux, and good preclinical pharmacokinetics (PK) and brain activity in animal models [22]. In the Phase 2 VANILLA study (NCT01793441), 12 weeks of treatment with balovaptan 4 mg or 10 mg daily in adult men with ASD resulted in clinically meaningful improvements vs placebo on the secondary endpoint, the Vineland-II™ Adaptive Behavior Scales composite score. However, the primary trial endpoint of an improved Social Responsiveness Scale–Second Edition (SRS-2) assessment was not met [23].
Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014–2017
Published in Clinical Toxicology, 2019
Joseph E. Carpenter, Brian Patrick Murray, Camille Dunkley, Ziad N. Kazzi, Melissa H. Gittinger
The term “designer benzodiazepine” is actually a bit of a misnomer, as the class includes benzodiazepine relatives and derivatives, namely thienodiazepines, triazolobenzodiazepines, and thienotriazolodiazepines (Figure 1) [8]. Notable members of this drug family include clonazolam, diclazepam, flubromazepam, flubromazolam, and pyrazolam [9]. None of these chemicals are approved by the United States Food and Drug Administration (FDA) for therapeutic use. Another benzodiazepine relative, etizolam, is approved for therapeutic use in some countries, but remains unapproved in the United States and has been reported to be a drug of abuse alongside other more novel agents [9,10].