Abstract
The GABAA receptor α2/α3 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 α1-, α2-, α3-, and α5-containing GABAA receptors and has partial agonist efficacy at the α2 and α3 but not the α1 or α5 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 [3H]flumazenil binding or [11C]flumazenil small-animal positron emission tomography (microPET) in rats, [123I]iomazenil γ-scintigraphy in rhesus monkeys, and [11C]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 (EC50) was calculated. The EC50 values for rats, rhesus monkeys, and baboons were all similar and ranged from 19 to 30 ng/ml, although in humans, the EC50 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 emphasize the relatively nonsedating nature of TPA023.
Footnotes
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↵1 Current affiliation: Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.
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↵2 Current affiliation: Amgen, Inc., Thousand Oaks, California.
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↵3 Current affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
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↵4 Current affiliation: Novartis, Horsham, Surrey, United Kingdom.
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↵5 Current affiliation: Pfizer Global Research and Development, Sandwich, Kent, United Kingdom.
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This work was funded by Merck.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.157909
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ABBREVIATIONS:
- L-838417
- 7-(1,1-dimethylethyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,5-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine
- TPA023 (also known at MK-0777)
- 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
- Occ50
- dose corresponding to 50% occupancy
- PET
- positron emission tomography
- Ro 15-1788
- 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester
- PEG
- polyethylene glycol
- EtOH
- ethanol
- MRK-409 (also know as MK-0343)
- 7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,6-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine
- TPA023B
- 6,2′-difluoro-5′-[3-(1-hydroxyl-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile
- SL65.1498
- 6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1-H-pyrido[3,4-b]indol-1-one
- α51A
- α5 subtype-selective triazolopthalazine 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-α]phthalazine.
- Received June 18, 2009.
- Accepted August 27, 2009.
- © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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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
