TPA023 Flashcards
What is TPA023?
Treatment developed by Merck for general anxiety disorder- is a traizolopyridazine GABA-A subtype a2/a3 partial agonist shown to have an anxiolytic effect comparable to benzodiazepines with reduced sedative side effects- binds with high affinity to the benzodiazepine binding site.
What is the efficacy of TPA023 at each of the subunits of the GABA-A receptor
binds with 0% efficacy to the a1 subunit, binds with 11% efficacy at a2, 21% efficacy at a3, 5% efficacy at a5
What are the side effects of benzodiazepines such as lorazepam and diazepam?
Cause memory impairment, cause sedation, have dependence ability,
What did mutagenesis studies show about the properties of each of the alpha subtypes?
a1- shown to have a sedatory effect
a2- shown to have anxiolytic and muscle relaxant effect a
a3- shown to have anxiolytic effect (at high affinity)
a5- shown to have an effect on cognition- activation causes a decrease in cognition
What in vitro data supports the use of TPA023?
Shown that TPA023 has a high affinity for a1,a2,a3,a5 subtypes and a relative efficacy of 11% and 21% at the a2 and a3 subtypes
What was the result of TPA023 in rats in the elevated plus maze?
Elevated plus maze- 30 minutes after dosing the rats were put on an elevated plus maze with arms in and outside; recorded movements for 5 mins; there was a significant treatment in rats on the percentage of time spent on the open arm and the distance travelled
What was the effect on rats of TPA023 in the fear potentiated startle?
Rats were trained to associate a red light with the occurrance of an electric shock; were then shown a light stimulus which potentiated fear and then a noise was sounded which caused startle behaviour
With TPA023, was shown startle response was significantly less when treated with 1 and 3mg/kg of TPA023
What was shown in the rat for the chain pulling assay?
Rats were starved and then strapped to a chain and presented with pellets. When treated even with 30mg/kg TPA023, there was no sedative effect, but with 3mg/kg diazepam there was sedative effect
What was shown in the mouse rotarod assay?
Mice were trained to walk on a rotating rod- only with 30mg/kg TPA023 were there any affects- diazepam 3mg/kg caused the mouse to fall after 75s
Conditioned emotional response in the squirrel monkey
Squirrel monkeys were trained to push a level to receive a fruit drink reward; after some time a red ligh cue was illuminated for 60s before an electric shock; when the monkey sees the red light it usually stops pressing the lever but with TPA023 it continued
What was shown in the baboon test of abuse potential?
Self-administration procedure was established with cocaine- then was replaced with TPA023 and lorazepam; was shown that baboons only pressed the lever 2/3 times for TPA023
What was shown about the binding activity of TPA023?
In rhesus monkeys and in humans, TPA023 displaced Flumazinil at 50% in humans with 2mg of TPA023
