Vanoxerine

Last updated

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

Vanoxerine is an investigational drug which is being evaluated for the treatment of heart arrhythmias 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).

Contents

Research

Treatment of 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. [1] [2]

Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptors, [3] and it has also been shown to reduce the consumption of alcohol in animal models of alcohol use disorder. [4]

Vanoxerine has been through human trials up to Phase II, [5] [6] [7] but development was stopped due to observed QTc 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. 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. [11]

Antiarrhythmic

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. [12]

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. [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]

Pharmacology

Mechanism of action

Vanoxerine 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, [16] but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects. [17] Vanoxerine has also been observed to be a potent blocker of the cardiac hERG repolarizing potassium channel (IKr) which has implicated Vanoxerine in having cardiotoxicity concerns. [14] Vanoxerine also binds with nanomolar affinity to the serotonin transporter. [18]

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]

Society and culture

History

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. [19] It was previously indicated as a treatment for Parkinson's disease and depression; however, it had no significant benefit with these diseases. [15]

Chemistry

Synthesis

Vanoxerine is a piperazine with two different alkyl sidechains attached. Its synthesis uses a tert-butyloxycarbonyl protecting group (Boc group) to mask the reactivity of one of its nitrogen atoms while the other is alkylated.

Vanoxerine synthesis.svg

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, a Grignard reaction using two equivalents of 4-fluorophenylmagnesium bromide (5) with ethyl formate (6) results in the formation of bis(4-fluorophenyl)methanol (7). Ether formation with 2-chloroethanol (8) in the presence of phosphoric acid gives the second alkylation partner (9). This is combined with (4) in a convergent synthesis to yield vanoxerine. [20] [21]

Related Research Articles

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

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 transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

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

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">WIN-35428</span> Chemical compound

WIN 35,428 is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is structurally derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies. While the naphthalenedisulfonate salt is the most commonly used form in scientific research due to its high solubility in water, the free base and hydrochloride salts are known compounds and can also be produced. The tartrate is another salt form that is reported.

<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">Troparil</span> Chemical compound

Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

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

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<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">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.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

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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.

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.

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<span class="mw-page-title-main">JJC8-091</span> Active component of a pharmaceutical drug

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References

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  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. 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.
  15. 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.
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  17. ↑ 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.
  18. ↑ Cararas SA, Izenwasser S, Wade D, Housman A, Verma A, Lomenzo SA, et al. (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.
  19. ↑ Glenn B (21 November 2011). "Drug developer ChanRx closes series A investment, hires CEO". MEDCITY News. Retrieved 11 March 2012.
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