Vanoxerine
Encyclopedia
Vanoxerine is a piperazine
derivative which is a potent and selective DRI
. GBR-12909 binds to the target site on the DAT
~ 500 times more strongly than cocaine
, but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects.
Vanoxerine has been researched for use in treating cocaine dependence
both as a substitute for cocaine and to block the rewarding effects. This strategy of using a competing agonist
with a longer half-life has been successfully used to treat addiction to opiates such as heroin by substituting with methadone
. It was hoped that vanoxerine would be of similar use in treating cocaine addiction.
Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptor
s, and it has also been shown to reduce the consumption of alcohol in animal models of alcohol abuse.
Vanoxerine has been through human trials up to Phase II, but development was halted after it was shown to cause long QT syndrome
.
However, GBR 12909 has not yet been completely abandoned and it appears hopeful new analogs are "around the corner".
As an example, GBR compounds are piperazine based and contain a proximal and a distal nitrogen. It was found that piperidine analogs are still fully active DRIs, although they don't have any affinity for the "piperazine binding site" unlike the GBR compounds. Further SAR
revealed that while there are 4 atoms connecting the two fluorophenyl rings to the piperazine, the ether in the chain could be omitted in exchange for a tertiary nitrogen.
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
derivative which is a potent and selective DRI
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
. GBR-12909 binds to the target site on the DAT
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
~ 500 times more strongly than cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects.
Vanoxerine has been researched for use in treating cocaine dependence
Cocaine dependence
Cocaine dependence is a psychological desire to regularly use cocaine. It can result in cardiovascular and brain damage such as constricting blood vessels in the brain, causing strokes and constricting arteries in the heart, causing heart attacks specifically in the central nervous system.The use...
both as a substitute for cocaine and to block the rewarding effects. This strategy of using a competing agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
with a longer half-life has been successfully used to treat addiction to opiates such as heroin by substituting with methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
. It was hoped that vanoxerine would be of similar use in treating cocaine addiction.
Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s, and it has also been shown to reduce the consumption of alcohol in animal models of alcohol abuse.
Vanoxerine has been through human trials up to Phase II, but development was halted after it was shown to cause long QT syndrome
Long QT syndrome
The long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
.
However, GBR 12909 has not yet been completely abandoned and it appears hopeful new analogs are "around the corner".
As an example, GBR compounds are piperazine based and contain a proximal and a distal nitrogen. It was found that piperidine analogs are still fully active DRIs, although they don't have any affinity for the "piperazine binding site" unlike the GBR compounds. Further SAR
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
revealed that while there are 4 atoms connecting the two fluorophenyl rings to the piperazine, the ether in the chain could be omitted in exchange for a tertiary nitrogen.