Tag: DRI: Dopamine Reuptake Inhibitor

What is Ethylphenidate?

Published on by Andrew MarshallLeave a comment

Introduction

Ethylphenidate (EPH) is a psychostimulant and a close analogue of methylphenidate.

Ethylphenidate acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft.

However, considering the close similarities between ethylphenidate and methylphenidate and the fact that methylphenidate, like cocaine, actually does not primarily act as a “classical” reuptake inhibitor, but rather as an “inverse agonist at the DAT” (also called a “negative allosteric modulator at the DAT”), it is at least very likely that ethylphenidate also primarily acts as an inverse DAT agonist instead of (or at least only secondarily) as a classical reuptake inhibitor (which could be called a “competitive antagonist at the DAT” using a similar terminology as “negative allosteric modulator at the DAT”, which per definition means that its mechanism is non-competitive).

Pharmacology

Pharmacokinetics

Ethylphenidate metabolises into methylphenidate and ritalinic acid.

Tiny amounts of ethylphenidate can be formed in vivo when ethanol and methylphenidate are coingested, via hepatic transesterification. Ethylphenidate formation appears to be more common when large quantities of methylphenidate and alcohol are consumed at the same time, such as in non-medical use or overdose scenarios. However, the transesterfication process of methylphenidate to ethylphenidate, as tested in mice liver, was dominant in the inactive (−)-enantiomer but showed a prolonged and increased maximal plasma concentration of the active (+)-enantiomer of methylphenidate. Additionally, only a small percent of the consumed methylphenidate is converted to ethylphenidate.

This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene.

Pharmacodynamics

All available data on ethylphenidate’s pharmacodynamics are drawn from studies conducted on rodents. Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound, but has significantly less activity on the norepinephrine transporter (NET). Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects.

The eudysmic ratio for ethylphenidate is superior to that of methylphenidate.

Legality

  • Ethylphenidate is a schedule II drug under the Convention on Psychotropic Substances.
  • Ethylphenidate is illegal in the Netherlands, as the Opium Law Lijst I covers it, as of 27 April 2018.
  • Ethylphenidate is not explicitly controlled in the US as part of the Controlled Substances Act but it could possibly be considered an analogue of a Schedule II substance (methylphenidate) under the Federal Analog Act if sold for human consumption.
    • In the United States, on 22 September 2023, the DEA filed a proposed rule for placement of Ethylphenidate into Schedule I status.
    • Public commenting opened on 22 September 2023, and closed on 21 November 2023.
  • Ethylphenidate is illegal in Sweden as of 15 December 2012.
  • Ethylphenidate is illegal to manufacture, distribute or import in the UK, as of 10 April 2015 it has been placed under a Temporary Class Drug Order which automatically places it in a Class-B-like category. Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year from 26 June 2016.
  • Ethylphenidate is illegal in Jersey under the Misuse of Drugs (Jersey) Law 1978.
  • Australian state and federal legislation contains provisions that mean that analogues of controlled drugs are also covered by the legislation. Ethylphenidate would be an analogue of methylphenidate under this legislation.
  • Ethylphenidate is controlled in Canada under the Controlled Drugs and Substances Act under Schedule III as of 05 May 2017.
  • Ethylphenidate is illegal in Germany as of 05 July 2013.
  • Ethylphenidate is illegal in Austria by the “Neue Psychoaktive Substanzen Gesetz” (=new psychoactive substances act) NPSG since 01 January 2012
  • Ethylphenidate is illegal in Denmark as of 01 February 2013.
  • Ethylphenidate is illegal in Poland by “the Act on Counteracting Drug Addiction” since 01 July 2015.
  • It is illegal in Lithuania to use, buy, possess, transport, sell or import Ethylphenidate from 2015.
  • As of October 2015 Ethylphenidate is a controlled substance in China.
  • In Finland ethylphenidate is scheduled in government decree on substances, preparations and plants considered to be narcotic drugs.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Ethylphenidate >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is a Dopamine Reuptake Inhibitor?

Published on by Andrew Marshall4 Comments

Introduction

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.

DRIs are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy for their psychostimulant effects, and in the treatment of obesity and binge eating disorder for their appetite suppressant effects. They are sometimes used as antidepressants in the treatment of mood disorders, but their use as antidepressants is limited given that strong DRIs have a high abuse potential and legal restrictions on their use. Lack of dopamine reuptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior given increase in dopaminergic neurotransmission. The dopaminergic pathways are considered to be strong reward centers. Many DRIs such as cocaine are drugs of abuse due to the rewarding effects evoked by elevated synaptic concentrations of dopamine in the brain.

Brief History

Until the 1950s, dopamine was thought to only contribute to the biosynthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain in similar levels as norepinephrine that the possibility was considered that its biological role might be other than the synthesis of the catecholamines.

Pharmacotherapeutic Uses

The following drugs have DRI action and have been or are used clinically specifically for this property: amineptine, dexmethylphenidate, difemetorex, fencamfamine, lefetamine, levophacetoperane, medifoxamine, mesocarb, methylphenidate, nomifensine, pipradrol, prolintane, and pyrovalerone.

The following drugs are or have been used clinically and possess only weak DRI action, which may or may not be clinically-relevant: adrafinil, armodafinil, bupropion, mazindol, modafinil, nefazodone, sertraline, and sibutramine.

The following drugs are or have been clinically used but only coincidentally have DRI properties: benzatropine, diphenylpyraline, etybenzatropine, ketamine, nefopam, pethidine (meperidine), and tripelennamine.

The following are a selection of some particularly notably abused DRIs: cocaine, ketamine, MDPV, naphyrone, and phencyclidine (PCP). Amphetamines, including amphetamine, methamphetamine, MDMA, cathinone, methcathinone, mephedrone, and methylone, are all DRIs as well, but are distinct in that they also behave, potentially more potently, as dopamine releasing agents (DRAs) (due to Yerkes–Dodson’s law, ‘more potently stimulated’ may not equal more optimally functionally stimulated). There are very distinct differences in the mode of action between dopamine releasers/substrates & dopamine re-uptake inhibitors; the former are functionally entropy-driven (i.e. relating to hydrophobicity) and the latter are enthalpy-driven (i.e. relating conformational change). Reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon oocytes that are naturally found on neurons, whereas releasing agents induce de-polarization of the neuron membrane.

The wakefulness-promoting agent modafinil and its analogues (e.g. adrafinil, armodafinil) have been approved to treat narcolepsy and shift work sleep disorder. These act as weak (micromolar) DRIs, but this effect does not correlate with wakefulness-promoting effects, suggesting the effect is too weak to be of clinical significance. The conclusion is these drugs promote wakefulness via some other mechanism.

DRIs have been explored as potential antiaddictive agents in the context of replacement therapy strategies, analogous to nicotine replacement for treating tobacco addiction and methadone replacement in the case of opioid addiction. DRIs have been explored as treatment for cocaine addiction, and have shown to alleviate cravings and self-administration.

Monoamine reuptake inhibitors, including DRIs, have shown effectiveness as therapy for excessive food intake and appetite control for obese patients. Though such pharmacotherapy is still available, the majority of stimulant anorectics marketed for this purpose have been withdrawn or discontinued due to adverse side effects such as hypertension, valvulopathy, and drug dependence.

List of DRIs

Only DRIs which are selective for the DAT over the other monoamine transporters (MATs) are listed below. For a list of DRIs that act at multiple MATs, see other monoamine reuptake inhibitor pages such as NDRI and SNDRI.

Selective Dopamine Reuptake Inhibitors

  • 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
  • Altropane (O-587)
  • Amfonelic acid (WIN 25978)
  • Amineptine (has a reasonable degree of selectivity for dopamine over norepinephrine reuptake inhibition)
  • BTCP (GK-13), same acronym as for breakthrough cancer pain.
  • 3C-PEP
  • DBL-583
  • Difluoropine (O-620)
  • GBR-12783
  • GBR-12935
  • GBR-13069
  • GBR-13098
  • GYKI-52895
  • Iometopane (β-CIT, RTI-55)
  • Ethylphenidate (more selective for DA vs NE reuptake inhibition compared to methylphenidate, but still has a marked effect on both)
  • Modafinil (relatively weak but very selective for the dopamine transporter, with little to no effect on the norepinephrine or serotonin transporters)
  • Armodafinil (R-enantiomer of modafinil; somewhat more potent at inhibiting DAT than racemic modafinil, with equally negligible action on NET and SERT)
  • RTI-229
  • Vanoxerine (GBR-12909)

DRIs with Substantial Activity at Other Sites

  • Adrafinil (weak, possibly stressful on liver)
  • Amantadine (also a weak NMDA receptor antagonist)
  • Benztropine (also muscarinic antagonist)
  • Bupropion (also a more potent NRI and likely NRA due to bupropion’s major metabolite hydroxybupropion)
  • Cocaine
  • Fluorenol (extremely weak)
  • Medifoxamine (relatively weak)
  • Metaphit (irreversible; depletes dopamine)
  • Methylphenidate (has a mild degree of selectivity for dopamine over norepinephrine reuptake inhibition, although it significantly affects both)
  • Nomifensine (Dual selective norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson’s disease.
  • Phenylpiracetam
  • Isopropylphenidate
  • Rimcazole
  • Venlafaxine (weak)
  • Solriamfetol (also norepinephrine reuptake inhibitor)

Other DRIs

  • Chaenomeles speciosa (Flowering quince)
  • Oroxylin A (found in Oroxylum indicum and Scutellaria baicalensis (Skullcap))

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.