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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

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. and Hargreaves, R. J. 2010. 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. Journal of Pharmacology and Experimental Therapeutics 332 (1) , pp. 17-25. 10.1124/jpet.109.157909

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Abstract

The GABAA receptor 2/3 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 1-, 2-, 3-, and 5-containing GABAA receptors and has partial agonist efficacy at the 2 and 3 but not the 1 or 5 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 -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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
ISSN: 0022-3565
Date of Acceptance: 27 August 2009
Last Modified: 14 Nov 2017 17:02
URI: http://orca.cf.ac.uk/id/eprint/105905

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