TPA-023B

TPA-023B is a high-affinity and orally active GABA_A receptor α2/α3 subtype (K_is of 0.73 nM/2 nM) partial agonist and a α1 subtype (K_i of 1.8 nM) antagonist. TPA-023B has non-sedating anxiolytic-like properties^[1]. In Vitro: TPA-023B also has high affinity for α5 subtype (K_i of 1.1 nM) of human recombinant GABA_A receptor, but over 1500-fold lower for the α4- and α6 containing subtypes (K_i > 1000 nM). TPA-023B also has a comparable affinity for native rat GABA_A receptors in different regions of the CNS (K_i 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 GABA_A 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].