Vanoxerine has been researched for use in treatingcocaine dependence both as a substitute for cocaine and to block the rewarding effects. This strategy of using a competingagonist with a longer half-life has been successfully used to treat addiction to opiates such asheroin by substituting withmethadone. It was hoped that vanoxerine would be of similar use in treating cocaine addiction.[1][2]
Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action atnicotinic acetylcholine receptors,[3] and it has also been shown to reduce the consumption of alcohol in animal models ofalcohol use disorder.[4]
Vanoxerine has been through human trials up to Phase II,[5][6][7] but development was stopped due to observedQTc effects in the context of cocaine use.[8]
However, vanoxerine analogs continue to be studied as treatments for cocaine addiction.[9][10] 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. FurtherSAR 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.[11]
Vanoxerine is a potentially effective treatment forabnormal heart rhythms. A significant cause of abnormal heart rhythms is reentry, an electrophysiologic event in which the proliferating signal refuses to terminate, and endures to preexcite the heart after the refractory period.[12]
It is likely that vanoxerine acts to prevent reentrant circuits. Vanoxerine terminatesatrial flutters andatrial fibrillations (both cardiac abnormal heart rhythms) by blocking the recirculating electrical signal, and preventing the reformation of the reentrant circuit.[13] 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.[14]
Experiments have successfully been performed on cell cultures,[citation needed] 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.[14] 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.[14]
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.[15]
Vanoxerine is a potent and selectivedopamine reuptake inhibitor (DRI). Vanoxerine binds to the target site on thedopamine transporter (DAT) ~ 50 times more strongly thancocaine,[17] but simultaneously inhibits the release of dopamine. This combined effect only slightly elevatesdopamine levels, giving vanoxerine only mild stimulant effects.[18] Vanoxerine has also been observed to be a potent blocker of the cardiachERG repolarizing potassium channel (IKr) which has implicated Vanoxerine in havingcardiotoxicity concerns.[14] Vanoxerine also binds with nanomolar affinity to the serotonin transporter.[19]
At a cellular level, vanoxerine acts to block cardiac ion channels.[15] Vanoxerine is a multichannel blocker, acting on IKr (potassium), L-type calcium and sodium ion channels.[15] 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.[15]
Vanoxerine is a drug that was in the midst of recruiting participants for a phase III human clinical trial for its use as a cardiac antiarrhythmic when safety concerns arose. It had passed phase IIb human trials without any concerns but the company, Laguna Pharmaceuticals, found safety issues which prompted them to shut down their company and the $30 million effort to produce a new heart medication.[20] It was previously indicated as a treatment forParkinson's disease anddepression; however, it had no significant benefit with these diseases.[15]
Vanoxerine is apiperazine with two differentalkyl sidechains attached. Its synthesis uses atert-butyloxycarbonyl protecting group (Boc group) to mask the reactivity of one of its nitrogen atoms while the other is alkylated.
Reaction of 1-Boc-piperazine (1) and (3-bromopropyl)benzene (2) gives (3) which, after removal of the Boc group using acid gives 1-(3-phenylpropyl)piperazine (4). Separately, aGrignard reaction using two equivalents of 4-fluorophenylmagnesium bromide (5) withethyl formate (6) results in the formation ofbis(4-fluorophenyl)methanol (7).Ether formation with2-chloroethanol (8) in the presence of phosphoric acid gives the second alkylation partner (9). This is combined with (4) in aconvergent synthesis to yield vanoxerine.[21][22]
^Szasz BK, Vizi ES, Kiss JP (March 2007). "Nicotinic acetylcholine receptor antagonistic property of the selective dopamine uptake inhibitor, GBR-12909 in rat hippocampal slices".Neuroscience.145 (1):344–9.doi:10.1016/j.neuroscience.2006.11.032.PMID17207584.S2CID25447970.
^Kamdar NK, Miller SA, Syed YM, Bhayana R,Gupta T, Rhodes JS (June 2007). "Acute effects of naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice".Psychopharmacology.192 (2):207–17.doi:10.1007/s00213-007-0711-5.PMID17273875.S2CID12497800.
^Søgaard U, Michalow J, Butler B, Lund Laursen A, Ingersen SH, Skrumsager BK, et al. (October 1990). "A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects".International Clinical Psychopharmacology.5 (4):237–51.doi:10.1097/00004850-199010000-00001.PMID2150527.S2CID32605858.
^Preti A (October 2000). "Vanoxerine National Institute on Drug Abuse".Current Opinion in Investigational Drugs.1 (2):241–51.PMID11249581.
^Herman BH, Elkashef A, Vocci F (2005). "Medications for the treatment of cocaine addiction: Emerging candidates".Drug Discovery Today.2 (1):87–92.doi:10.1016/j.ddstr.2005.05.014.
^Runyon SP, Carroll FI (2006). "Dopamine transporter ligands: recent developments and therapeutic potential".Current Topics in Medicinal Chemistry.6 (17):1825–43.doi:10.2174/156802606778249775.PMID17017960.
^Tanda G, Bassareo V, Di Chiara G (January 1996). "Mianserin markedly and selectively increases extracellular dopamine in the prefrontal cortex as compared to the nucleus accumbens of the rat".Psychopharmacology.123 (2):127–30.doi:10.1007/bf02246169.PMID8741935.S2CID43300151.
^Matsumoto N, Khrestian CM, Ryu K, Lacerda AE, Brown AM, Waldo AL (March 2010). "Vanoxerine, a new drug for terminating atrial fibrillation and flutter".Journal of Cardiovascular Electrophysiology.21 (3):311–9.doi:10.1111/j.1540-8167.2009.01622.x.PMID19817929.S2CID32305356.
^Yates JR (2024)."Pharmacological Treatments for Methamphetamine Use Disorder: Current Status and Future Targets".Subst Abuse Rehabil.15:125–161.doi:10.2147/SAR.S431273.PMC11370775.PMID39228432.Modafinil is an anti-narcoleptic drug that acts as a weak dopamine transporter (DAT) inhibitor.99 Modafinil decreases METH self-administration and attenuates drug-seeking behavior in rodents.100–103 These effects may not be completely mediated by inhibition of DAT, as administration of the highly selective DAT inhibitor GBR 12909 potentiates METH-induced increases in locomotor activity and reinstatement of METH seeking.104,105
^Izenwasser S, Werling LL, Cox BM (June 1990). "Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex".Brain Research.520 (1–2):303–9.doi:10.1016/0006-8993(90)91719-W.PMID2145054.S2CID24436917.
^Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists".Chemical Reviews.100 (3):925–1024.doi:10.1021/cr9700538.PMID11749256.
^Matecka D, Rothman RB, Radesca L, de Costa BR, Dersch CM, Partilla JS, et al. (November 1996). "Development of novel, potent, and selective dopamine reuptake inhibitors through alteration of the piperazine ring of 1-[2-(diphenylmethoxy)ethyl]-and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)".Journal of Medicinal Chemistry.39 (24):4704–4716.doi:10.1021/jm960305h.PMID8941383.
^Ironside MD, Sugathapala PM, Robertson J, Darey MC, Zhang J (2002). "Scale-Up Synthesis of the Dopamine Uptake Inhibitor GBR-12909".Organic Process Research & Development.6 (5):621–627.doi:10.1021/op020211j.
