TPA023B

Names

[ Name ]:
TPA023B

[Synonym ]:
MFCD30532602
2',6-Difluoro-5'-[3-(2-hydroxy-2-propanyl)imidazo[1,2-b][1,2,4]triazin-7-yl]-2-biphenylcarbonitrile
TPA-023B
2',6-Difluoro-5'-[3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile
[1,1'-Biphenyl]-2-carbonitrile, 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]-

Biological Activity

[Description]:

TPA023B is a potent, α2/α3 subtype-selective GABAA receptor partial agonist with Ki of 2.0 and 1.8 nM, does not affect the functioning of the α1 subtype; demonstrates anxiolytic effects in rodent and primate models of anxiety, with no significant effects in ataxia and/or myorelaxation.

[Related Catalog]:

Signaling Pathways >> Membrane Transporter/Ion Channel >> GABA Receptor

Research Areas >> Neurological Disease

Signaling Pathways >> Neuronal Signaling >> GABA Receptor

[In Vitro]

TPA-023B also has high affinity for α5 subtype (Ki of 1.1 nM) of human recombinant GABAA receptor, but over 1500-fold lower for the α4- and α6 containing subtypes (Ki > 1000 nM). TPA-023B also has a comparable affinity for native rat GABAA receptors in different regions of the CNS (Ki of 0.32-0.99 nM in cerebellum, spinal cord and frontal cortex)[1]. TPA-023B antagonizes the ability of chlordiazepoxide to potentiate the GABA EC20-induced current in cells expressing the α1 subtype. More specifically, 3 μM chlordiazepoxide potentiates the GABA EC20 current by 105% and this effect could be reduced to 8% in the presence of 100 nM TPA-023B[1].

[In Vivo]

TPA-023B gives dose- and time-dependent occupancy of rat brain GABAA receptors as measured using an in vivo [3H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL[1]. TPA-023B is anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet has no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%[1].

[References]

[1]. Atack JR, et al. Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol. 2011 Mar;25(3):329-44.

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Molecular Formula ]:
C₂₁H₁₅F₂N₅O

[ Molecular Weight ]:
391.374

[ Exact Mass ]:
391.124481

[ LogP ]:
1.36

[ Index of Refraction ]:
1.658