TPA-023
Encyclopedia
TPA-023 is an anxiolytic
drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine
drugs, but is structurally distinct and so is classed as a nonbenzodiazepine
anxiolytic. It is a subtype-selective, mixed agonist-antagonist at GABAA receptor
s, which acts as a partial agonist
at the α2 and α3 subtypes, but as a silent antagonist at α1 and α5 subtypes. It has primarily anxiolytic
and anticonvulsant
effects in animal tests, but with no sedative
effects even at 50x the effective anxiolytic dose.
In human trials on healthy volunteers, TPA-023 was comparable to lorazepam
, but had much less side effects on cognition, memory, alertness or coordination. In Phase II trials, the compound was significantly superior to placebo without inducing sedation. The clinical development was halted due to preclinical toxicity (cataract) in long term dosing studies. GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer. CNS Neuroscience and Therapeutics. 2008 Spring;14(1):25-35. PMID 18482097 TPA-023 is well absorbed following oral administration and extensively metabolised by the liver, with a half-life of 6.7 hours. The main enzyme involved in its metabolism is CYP3A4
, with some contribution by CYP3A5
.
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugs, but is structurally distinct and so is classed as a nonbenzodiazepine
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
anxiolytic. It is a subtype-selective, mixed agonist-antagonist at GABAA receptor
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
s, which acts as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
at the α2 and α3 subtypes, but as a silent antagonist at α1 and α5 subtypes. It has primarily anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
and anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
effects in animal tests, but with no sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
effects even at 50x the effective anxiolytic dose.
In human trials on healthy volunteers, TPA-023 was comparable to lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
, but had much less side effects on cognition, memory, alertness or coordination. In Phase II trials, the compound was significantly superior to placebo without inducing sedation. The clinical development was halted due to preclinical toxicity (cataract) in long term dosing studies. GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer. CNS Neuroscience and Therapeutics. 2008 Spring;14(1):25-35. PMID 18482097 TPA-023 is well absorbed following oral administration and extensively metabolised by the liver, with a half-life of 6.7 hours. The main enzyme involved in its metabolism is CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, with some contribution by CYP3A5
CYP3A5
Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:...
.