Benzodiazepine Binding Site Occupancy by the Novel GABAA Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in Rats, Primates, and Humans
Abstract
The GABA(A) receptor alpha2/alpha3 subtype-selective compound 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023; also known as MK-0777) is a triazolopyridazine that has similar, subnanomolar affinity for the benzodiazepine binding site of alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors and has partial agonist efficacy at the alpha2 and alpha3 but not the alpha1 or alpha5 subtypes. The purpose of the present study was to define the relationship between plasma TPA023 concentrations and benzodiazepine binding site occupancy across species measured using various methods. Thus, occupancy was measured using either in vivo [(3)H]flumazenil binding or [(11)C]flumazenil small-animal positron emission tomography (microPET) in rats, [(123)I]iomazenil gamma-scintigraphy in rhesus monkeys, and [(11)C]flumazenil PET in baboons and humans. For each study, plasma-occupancy curves were derived, and the plasma concentration of TPA023 required to produce 50% occupancy (EC(50)) was calculated. The EC(50) values for rats, rhesus monkeys, and baboons were all similar and ranged from 19 to 30 ng/ml, although in humans, the EC(50) was slightly lower at 9 ng/ml. In humans, a single 2-mg dose of TPA023 produced in the region of 50 to 60% occupancy in the absence of overt sedative-like effects. Considering that nonselective full agonists are associated with sedation at occupancies of less than 30%, these data emp…
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Species differences in subunit composition, distribution, and pharmacokinetics may exist between non-human primates and humans.
“while receptor pharmacology is broadly comparable, species differences in subunit composition, distribution, and pharmacokinetics may exist (Atack et al., 2010; Friedman, Redmond, & Greenblatt, 1991).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Atack et al., 2010
The PET imaging data used to model the dose-occupancy curve come from non-human primates rather than humans.
“The PET imaging data used to model the dose-occupancy curve come from non-human primates rather than humans; while receptor pharmacology is broadly comparable, species differences in subunit composition, distribution, and pharmacokinetics may exist (Atack et al., 2010; Friedman, Redmond, & Greenblatt, 1991).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Atack et al., 2010
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“…data used to model the dose-occupancy curve come from non-human primates rather than humans; while receptor pharmacology is broadly comparable, species differences in subunit composition, distribution, and pharmacokinetics may exist (Atack et al., 2010; Friedman, Redmond, & Greenblatt, 1991).”
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- Authors
- Atack, J. R., Wong, D. F., Fryer, T. D., Ryan, C., Sanabria, S., Zhou, Y., Dannals, R. F., Eng, W.-S., Gibson, R. E., Burns, H. D., Vega, J. M., Vessy, L., Scott-Stevens, P., Beech, J. S., Baron, J.-C., Sohal, B., Schrag, M. L., Aigbirhio, F. I., McKernan, R. M., & Hargreaves, R. J.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Johns Hopkins University (US)
- University of Cambridge (GB)
- Novartis (Switzerland) (CH)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 332
- Issue
- 1
- Pages
- 17-25
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2044558761
- Cited by
- 36
- References
- 41
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 3 · 2021: 1 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 5 · 2012: 2
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0508-10327)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and pharmacology of benzodiazepine derivatives
- Keywords
- EC50, triazolopyridazines, species comparison, sedation, partial agonists, benzodiazepine receptor
- MeSH terms
- Animals, Binding Sites, Brain, Dose-Response Relationship, Drug, Flumazenil, Humans, Macaca mulatta, Papio, Protein Binding, Pyridazines, Radioligand Assay, Species Specificity, Tissue Distribution, Triazoles, GABA Agonists, Protein Subunits, Positron-Emission Tomography, Rats, GABA-A Receptor Agonists, GABA-A Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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