Vanoxerine

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Vanoxerine
Vanoxerine.svg
Vanoxerine ball-and-stick.png
Clinical data
Other namesGBR-12909
ATC code
  • None
Pharmacokinetic data
Elimination half-life 6 hours approx
Identifiers
  • 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C28H32F2N2O
Molar mass 450.574 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)C(OCCN2CCN(CC2)CCCc3ccccc3)c4ccc(F)cc4
  • InChI=1S/C28H32F2N2O/c29-26-12-8-24(9-13-26)28(25-10-14-27(30)15-11-25)33-22-21-32-19-17-31(18-20-32)16-4-7-23-5-2-1-3-6-23/h1-3,5-6,8-15,28H,4,7,16-22H2 Yes check.svgY
  • Key:NAUWTFJOPJWYOT-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Vanoxerine is a piperazine derivative which is a potent and selective dopamine reuptake inhibitor (DRI). Vanoxerine binds to the target site on the dopamine transporter (DAT) ~ 50 times more strongly than cocaine, [1] but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects. [2] Vanoxerine has also been observed to be a potent blocker of the IKr (hERG) channel. [3] Vanoxerine also binds with nanomolar affinity to the serotonin transporter. [4]

Contents

Vanoxerine as a treatment for cocaine dependence

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. [5] [6]

Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptors, [7] and it has also been shown to reduce the consumption of alcohol in animal models of alcohol use disorder. [8]

Vanoxerine has been through human trials up to Phase II, [9] [10] [11] but development was stopped due to observed QTc effects in the context of cocaine use. [12]

However, vanoxerine analogs continue to be studied as treatments for cocaine addiction. [13] [14] 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. [15]

Vanoxerine as an antiarrhythmic

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. [16] It was previously indicated as a treatment for Parkinson's disease and depression; however, it had no significant benefit with these diseases. [17]

Medical uses

Vanoxerine is a potentially effective treatment for abnormal 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. [18]

It is likely that vanoxerine acts to prevent reentrant circuits. Vanoxerine terminates atrial flutters and atrial fibrillations (both cardiac abnormal heart rhythms) by blocking the recirculating electrical signal, and preventing the reformation of the reentrant circuit. [19] 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. [3]

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. [3] 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. [3]

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. [17]

Cellular mechanism

At a cellular level, vanoxerine acts to block cardiac ion channels. [17] Vanoxerine is a multichannel blocker, acting on IKr (potassium), L-type calcium and sodium ion channels. [17] 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. [17]

Molecular mechanism

At this time, little is known about the molecular mechanism of vanoxerine, and steps are being made towards understanding how vanoxerine operates on a molecular level.

Related Research Articles

<span class="mw-page-title-main">Cardioversion</span> Conversion of a cardiac arrhythmia to a normal rhythm using an electrical shock or medications

Cardioversion is a medical procedure by which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal rhythm using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart at a specific moment in the cardiac cycle, restoring the activity of the electrical conduction system of the heart. Pharmacologic cardioversion, also called chemical cardioversion, uses antiarrhythmia medication instead of an electrical shock.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

<span class="mw-page-title-main">FOSB</span> Protein

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.

<span class="mw-page-title-main">Dimethocaine</span> Stimulant

Dimethocaine, also known as DMC or larocaine, is a compound with a stimulatory effect. This effect resembles that of cocaine, although dimethocaine appears to be less potent. Just like cocaine, dimethocaine is addictive due to its stimulation of the reward pathway in the brain. However, dimethocaine is a legal cocaine replacement in some countries and is even listed by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) under the category “synthetic cocaine derivatives”. The structure of dimethocaine, being a 4-aminobenzoic acid ester, resembles that of procaine. It is found as a white powder at room temperature.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">RTI-336</span> Chemical compound

RTI(-4229)-336, is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine, however it produces relatively mild stimulant effects, with a slow onset and long duration of action. These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs, and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.

<span class="mw-page-title-main">Michel Haïssaguerre</span>

Michel Haïssaguerre is a French cardiologist and electrophysiologist. His investigations have been the basis for development of new markers and therapies for atrial and ventricular fibrillation.

<span class="mw-page-title-main">GBR-12935</span> Chemical compound

GBR-12935 is a piperazine derivative which is a potent and selective dopamine reuptake inhibitor. It was originally developed in its 3H radiolabelled form for the purpose of mapping the distribution of dopaminergic neurons in the brain by selective labelling of dopamine transporter proteins. This has led to potential clinical uses in the diagnosis of Parkinson's disease, although selective radioligands such as Ioflupane (¹²³I) are now available for this application. GBR-12935 is now widely used in animal research into Parkinson's disease and the dopamine pathways in the brain.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

<span class="mw-page-title-main">1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine</span> Chemical compound

1-Benzyl-4-[2-(diphenyl​methoxy)​ethyl]​piperidine is a stimulant of the piperidine class which acts as a potent and selective dopamine reuptake inhibitor. It is closely related to vanoxerine and GBR-12,935, which in contrast are piperazines.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">JHW-007</span> Atypical dopamine reuptake inhibitor

JHW-007 is a cocaine analog and a high affinity atypical dopamine reuptake inhibitor that is being researched for the treatment of cocaine addiction. JHW-007 has been found to blunt the psychostimulatory effects of cocaine and reduce self-administration in rodents. JHW-007 exposure has been shown to block the conditioned place preference effects of cocaine. JHW-007 may directly antagonize the autoregulatory dopamine D2 receptor, a hypothesis that was developed following the observation of JHW-007's ability to inhibit D2 receptor-mediated currents in the midbrain.

References

  1. ↑ 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. PMID   2145054. S2CID   24436917.
  2. ↑ Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID   11749256.
  3. 1 2 3 4 Cakulev I, Lacerda AE, Khrestian CM, Ryu K, Brown AM, Waldo AL (November 2011). "Oral vanoxerine prevents reinduction of atrial tachyarrhythmias: preliminary results". Journal of Cardiovascular Electrophysiology. 22 (11): 1266–73. doi:10.1111/j.1540-8167.2011.02098.x. PMC   3172341 . PMID   21615815.
  4. ↑ Cararas SA, Izenwasser S, Wade D, Housman A, Verma A, Lomenzo SA, Trudell ML (December 2011). "Further structure-activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters". Bioorganic & Medicinal Chemistry. 19 (24): 7551–8. doi:10.1016/j.bmc.2011.10.028. PMC   3230044 . PMID   22055716.
  5. ↑ Vetulani J (2001). "Drug addiction. Part III. Pharmacotherapy of addiction" (PDF). Polish Journal of Pharmacology. 53 (5): 415–34. PMID   11990060.
  6. ↑ Preti A (June 2007). "New developments in the pharmacotherapy of cocaine abuse". Addiction Biology. 12 (2): 133–51. doi:10.1111/j.1369-1600.2007.00061.x. PMID   17508985. S2CID   21834607.
  7. ↑ 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. PMID   17207584. S2CID   25447970.
  8. ↑ 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. PMID   17273875. S2CID   12497800.
  9. ↑ Søgaard U, Michalow J, Butler B, Lund Laursen A, Ingersen SH, Skrumsager BK, Rafaelsen OJ (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. PMID   2150527. S2CID   32605858.
  10. ↑ Preti A (October 2000). "Vanoxerine National Institute on Drug Abuse". Current Opinion in Investigational Drugs. 1 (2): 241–51. PMID   11249581.
  11. ↑ Gorelick DA, Gardner EL, Xi ZX (2004). "Agents in development for the management of cocaine abuse". Drugs. 64 (14): 1547–73. doi:10.2165/00003495-200464140-00004. PMID   15233592. S2CID   5421657.
  12. ↑ 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.
  13. ↑ Rothman RB, Baumann MH, Prisinzano TE, Newman AH (January 2008). "Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction". Biochemical Pharmacology. 75 (1): 2–16. doi:10.1016/j.bcp.2007.08.007. PMC   2225585 . PMID   17897630.
  14. ↑ 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. PMID   17017960.
  15. ↑ 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. PMID   8741935. S2CID   43300151.
  16. ↑ Glenn B (21 November 2011). "Drug developer ChanRx closes series A investment, hires CEO". MEDCITY News. Retrieved 11 March 2012.
  17. 1 2 3 4 5 Lacerda AE, Kuryshev YA, Yan GX, Waldo AL, Brown AM (March 2010). "Vanoxerine: cellular mechanism of a new antiarrhythmic". Journal of Cardiovascular Electrophysiology. 21 (3): 301–10. doi:10.1111/j.1540-8167.2009.01623.x. PMC   3107714 . PMID   19817928.
  18. ↑ Mahmud F, Shiozawa N, Makikawa M, Nomura T (June 2011). "Reentrant excitation in an analog-digital hybrid circuit model of cardiac tissue". Chaos. 21 (2): 023121. Bibcode:2011Chaos..21b3121M. doi:10.1063/1.3597645. PMID   21721763.
  19. ↑ 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. PMID   19817929. S2CID   32305356.
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