Vanoxerine

Vanoxerine (GBR-12909) 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 receptors, 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.