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.
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 emphasize the relatively nonsedating nature of TPA023.
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom. jatack1@its.jnj.com.
John R
JR
Atack
Dean F
DF
Wong
Tim D
TD
Fryer
Christine
C
Ryan
Sandra
S
Sanabria
Yun
Y
Zhou
Robert F
RF
Dannals
Wai-si
WS
Eng
Raymond E
RE
Gibson
H Donald
HD
Burns
Jose M
JM
Vega
Laura
L
Vessy
Paul
P
Scott-Stevens
John S
JS
Beech
Jean-Claude
JC
Baron
Bindi
B
Sohal
Michael L
ML
Schrag
Franklin I
FI
Aigbirhio
Ruth M
RM
McKernan
Richard J
RJ
Hargreaves
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000097:blood / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D008253:Macaca mulatta; D010215:Papio; D049268:Positron-Emission Tomography; D011485:Protein Binding; D021122:Protein Subunits; D011724:Pyridazines / Q000097:blood / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution; D014230:Triazoles / Q000097:blood / Q000494:pharmacology*
C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D021122:Protein Subunits; D011724:Pyridazines; D014230:Triazoles; D005442:Flumazenil