Product Code Database
Vanoxerine is an investigational drug which is being evaluated for the treatment of and cocaine dependence. Vanoxerine is a piperazine derivative which has multiple pharmacological activities including acting as an dopamine reuptake inhibitor, serotonin transporter inhibitor, and as a blocker of the cardiac hERG repolarizing potassium channel (IKr).
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 use disorder.
Vanoxerine has been through human trials up to Phase II, but development was stopped due to observed QTc effects in the context of cocaine use.
However, vanoxerine analogs continue to be studied as treatments for cocaine addiction. 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 do not 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. Vanoxerine, a blocker of the dopamine carrier devoid of action on the noradrenaline carrier, while greatly increasing dopamine in the nucleus accumbens, is ineffective in raising extracellular dopamine in the prefrontal cortex.
It is likely that vanoxerine acts to prevent reentrant circuits. Vanoxerine terminates and atrial fibrillations (both cardiac abnormal heart rhythms) by blocking the recirculating electrical signal, and preventing the reformation of the reentrant circuit. Vanoxerine has also shown a tendency to reduce the recurrence of cardiac arrhythmias, as it was exceedingly difficult to reproduce an atrial flutter or fibrillation in a subject that had been taking vanoxerine.
Experiments have successfully been performed on cell cultures, canine hosts and testing has moved towards human trials.
In clinical human trials with increasing dosages, vanoxerine has shown to have a highly favourable therapeutic index, showing no side effects at concentrations much higher than the therapeutic dose. In canines, the effective therapeutic dose was between 76 ng/ml and 99 ng/ml, however the drug reached plasma concentrations of 550 ng/ml without harmful side effects, presenting a desirable therapeutic index.
One of the major benefits of vanoxerine is that it does not appear to cause the same harmful side effects as its most comparable contender, amiodarone.
At a cellular level, vanoxerine acts to block cardiac ion channels. Vanoxerine is a multichannel blocker, acting on IKr (potassium), L-type calcium and sodium ion channels. By blocking these specific channels, there is a prolongation of the action potential of the cell, preventing reactivation by a reentrant circuit. The block is strongly frequency dependant: as the pacing of the heart increases so does the frequency of ion channel blocking by vanoxerine.
|
|
