Ethylphenidate

Last updated
Ethylphenidate
Ethylphenidate.svg
Ethylphenidate-3D-ball-model.png
Clinical data
Routes of
administration 		By mouth, insufflation, inhalation, sublingual, rectal, intramuscular, intravenous
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Bioavailability Variable
Protein binding Unknown
Metabolism Hepatic transesterification of prodrugs methylphenidate and ethanol
Excretion Urine, sweat
Identifiers
  • (RS)-Ethyl 2-phenyl-2-piperidin-2-ylacetate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C15H21NO2
Molar mass 247.338 g·mol−1
3D model (JSmol)
  • CCOC(=O)C(C1CCCCN1)C2=CC=CC=C2
  • InChI=1S/C15H21NO2/c1-2-18-15(17)14(12-8-4-3-5-9-12)13-10-6-7-11-16-13/h3-5,8-9,13-14,16H,2,6-7,10-11H2,1H3 Yes check.svgY
  • Key:AIVSIRYZIBXTMM-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ethylphenidate (EPH) is a central nervous system (CNS) stimulant and a close analog of methylphenidate.

Contents

Ethylphenidate acts as a norepinephrine–dopamine 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.

Ethylphenidate, being almost identical to methylphenidate in both structure and pharmacodynamics, likely also doesn't solely act as a "classical" reuptake inhibitor but primarily as an inverse agonist at the dopamine transporter (DAT), inducing dopamine transporter reversal and subsequent dopamine release from the axon terminal into the synaptic cleft in a manner similar to but distinct from amphetamines. [3]

Pharmacology

Pharmacokinetics

Ethylphenidate metabolizes into methylphenidate and ritalinic acid. [4]

Tiny amounts of ethylphenidate can be formed in vivo when ethanol and methylphenidate are coingested, via hepatic transesterification. [5] 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. [6] 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. [7] Additionally, only a small percentage of the consumed methylphenidate is converted to ethylphenidate. [5]

This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene. [8]

Pharmacodynamics

All available data on ethylphenidate's pharmacodynamics are drawn from studies conducted on rodents.[ citation needed ] Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound, [7] but has significantly less activity on the norepinephrine transporter (NET). [9] Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects. [10]

The eudysmic ratio for ethylphenidate is superior to that of methylphenidate. [7] [ failed verification ]

The following is ethylphenidate's binding profile in the mouse, alongside methylphenidate's. Figures for both the racemic and the dextrorotary enantiomers are given: [9]

CompoundBinding DAT

Ki (nM)

Binding NET

Ki (nM)

Uptake DA

IC50 (nM)

Uptake NE

IC50 (nM)

d-methylphenidate1394082846
d-ethylphenidate276247924247
dl-methylphenidate10515602431
dl-ethylphenidate382482482408

Legality

See also

Related Research Articles

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a first-line treatment for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.

<span class="mw-page-title-main">Methcathinone</span> Psychoactive stimulant

Methcathinone is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone. It is used as a recreational drug due to its potent stimulant and euphoric effects and is considered to be addictive, with both physical and psychological withdrawal occurring if its use is discontinued after prolonged or high-dosage administration. It is usually snorted, but can be smoked, injected, or taken orally.

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">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

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

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

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

Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver when cocaine and ethanol coexist in the blood. In 1885, cocaethylene was first synthesized, and in 1979, cocaethylene's side effects were discovered.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

<span class="mw-page-title-main">HDMP-28</span> Stimulant drug

HDMP-28 or methylnaphthidate is a piperidine based stimulant drug, closely related to methylphenidate, but with the benzene ring replaced by naphthalene. It is a potent dopamine reuptake inhibitor, with several times the potency of methylphenidate and a short duration of action, and is a structural isomer of another potent dopamine reuptake inhibitor, N,O-Dimethyl-4-(2-naphthyl)piperidine-3-carboxylate. It has been sold as a designer drug since around 2015.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A 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. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">3-Fluoroamphetamine</span> Stimulant drug that acts as an amphetamine

3-Fluoroamphetamine is a stimulant drug from the amphetamine family which acts as a monoamine releaser with similar potency to methamphetamine but more selectivity for dopamine and norepinephrine release over serotonin. It is self-administered by mice to a similar extent to related drugs such as 4-fluoroamphetamine and 3-methylamphetamine.

<span class="mw-page-title-main">3,4-Dichloromethylphenidate</span> Stimulant drug

3,4-dichloromethylphenidate is a potent stimulant drug from the phenidate class closely related to methylphenidate. It acts as a potent serotonin-norepinephrine-dopamine reuptake inhibitor with a long duration of action. It has been sold online as a designer drug.

<span class="mw-page-title-main">4-Methylmethylphenidate</span> Stimulant drug

threo-4-Methylmethylphenidate (4-MeTMP) is a stimulant drug related to methylphenidate. It is slightly less potent than methylphenidate and has relatively low efficacy at blocking dopamine reuptake despite its high binding affinity, which led to its investigation as a possible substitute drug for treatment of stimulant abuse. On the other hand, several other simple ring-substituted derivatives of threo-methylphenidate such as the 4-fluoro and 3-chloro compounds are more potent than methylphenidate both in efficacy as dopamine reuptake inhibitors and in animal drug discrimination assays.

<span class="mw-page-title-main">6-APB</span> Psychoactive drug

6-APB is an empathogenic psychoactive drug of the substituted benzofuran and substituted phenethylamine classes. 6-APB and other compounds are sometimes informally called "Benzofury" in newspaper reports. It is similar in structure to MDA, but differs in that the 3,4-methylenedioxyphenyl ring system has been replaced with a benzofuran ring. 6-APB is also the unsaturated benzofuran derivative of 6-APDB. It may appear as a tan grainy powder.

<span class="mw-page-title-main">Methiopropamine</span> Structural analog of methamphetamine

Methiopropamine (MPA), also known as N-methylthiopropamine, is an organic compound structurally related to methamphetamine. Originally reported in 1942, the molecule consists of a thiophene group with an alkyl amine substituent at the 2-position. It appeared for public sale in the United Kingdom in December 2010 as a "research chemical" or "legal high", recently branded as Blow. It has limited popularity as a recreational stimulant.

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">3-Methylmethcathinone</span> Substituted cathinone designer drug

3-Methylmethcathinone (3-MMC), also known as metaphedrone, is a designer drug from the substituted cathinone family. 3-MMC is a monoamine transporter substrate that potently releases and inhibits the reuptake of dopamine and norepinephrine, as well as displaying moderate serotonin releasing activity. Unlike some synthetic cathinones, 3-MMC has been evaluated in at least one large mammal study.

<span class="mw-page-title-main">HDEP-28</span> Stimulant drug

HDEP-28 or ethylnaphthidate is a piperidine based stimulant drug, closely related to ethylphenidate, but with the benzene ring replaced by naphthalene. It is even more closely related to HDMP-28, which acts as a potent serotonin–norepinephrine–dopamine reuptake inhibitor with several times the potency of methylphenidate and a short duration of action. It has been sold as a designer drug since around 2015.

<span class="mw-page-title-main">1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine</span> Chemical compound

1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine (3C-PEP) is a designer drug of the piperazine class of chemical substances. 3C-PEP is related to meta-cholorophenylpiperazine (mCPP) and phenethylamine that can be thought of as mCPP having a phenylethyl group attached to the nitrogen atom at its 4-position. It was first described in 1994 in a patent disclosing a series of piperazine compounds as sigma receptor ligands. Later, it was discovered to be a highly potent dopamine reuptake inhibitor.

<span class="mw-page-title-main">4-Fluoromethylphenidate</span> Chemical compound

4-Fluoromethylphenidate is a stimulant drug that acts as a higher potency dopamine reuptake inhibitor than the closely related methylphenidate.

References

  1. ↑ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ↑ "Substance Details Ethylphenidate" . Retrieved 2024-01-22.
  3. ↑ Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. CNS Stimulants. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID   24953830.
  4. ↑ Negreira N, Erratico C, van Nuijs AL, Covaci A (January 2016). "Identification of in vitro metabolites of ethylphenidate by liquid chromatography coupled to quadrupole time-of-flight mass spectrometry". Journal of Pharmaceutical and Biomedical Analysis. 117 (5): 474–84. doi:10.1016/j.jpba.2015.09.029. hdl: 10067/1301870151162165141 . PMID   26454340.
  5. 1 2 Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS (June 2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug Metabolism and Disposition. 28 (6): 620–4. PMID   10820132.
  6. ↑ Markowitz JS, Logan BK, Diamond F, Patrick KS (August 1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion". Journal of Clinical Psychopharmacology. 19 (4): 362–6. doi:10.1097/00004714-199908000-00013. PMID   10440465.
  7. 1 2 3 Patrick KS, Williard RL, VanWert AL, Dowd JJ, Oatis JE, Middaugh LD (April 2005). "Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol". Journal of Medicinal Chemistry. 48 (8): 2876–81. doi:10.1021/jm0490989. PMID   15828826.
  8. ↑ Bourland JA, Martin DK, Mayersohn M (December 1997). "Carboxylesterase-mediated transesterification of meperidine (Demerol) and methylphenidate (Ritalin) in the presence of [2H6]ethanol: preliminary in vitro findings using a rat liver preparation". Journal of Pharmaceutical Sciences. 86 (12): 1494–6. doi:10.1021/js970072x. PMID   9423167.
  9. 1 2 Williard RL, Middaugh LD, Zhu HJ, Patrick KS (February 2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology. 18 (1): 39–51. doi:10.1097/FBP.0b013e3280143226. PMID   17218796. S2CID   20232871.
  10. ↑ Jatlow P, Elsworth JD, Bradberry CW, Winger G, Taylor JR, Russell R, Roth RH (1991). "Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion" (PDF). Life Sciences. 48 (18): 1787–94. doi:10.1016/0024-3205(91)90217-Y. hdl: 2027.42/29671 . PMID   2020260.
  11. 1 2 "Schedules of Controlled Substances: Placement of Ethylphenidate in Schedule I" (PDF). Federal Register . 88 (183): 65,332. 22 September 2023. Retrieved 16 October 2023.
  12. ↑ "Opiumwet" [Opium Act]. Ministerie van Binnenlandse Zaken en Koninkrijksrelaties[Ministry of the Interior and Kingdom Relations] (in Dutch). Retrieved 30 January 2022.
  13. ↑ https://www.alabamapublichealth.gov/blog/assets/controlledsubstanceslist.pdf [ bare URL PDF ]
  14. ↑ "'Legal highs' to be banned under temporary power". Gov.uk.
  15. ↑ "Re: TCDOs and ACMD position on methylphenidate-based NPS" (PDF). Gov.uk. 2016-02-29. Retrieved 2016-11-28.
  16. ↑ "Misuse of Drug (General Provisions) (Jersey) Order 2009". Jersey Legal Information Board . January 2014. Retrieved 2023-09-28.
  17. ↑ Parks C, McKeown D, Torrance HJ (December 2015). "A review of ethylphenidate in deaths in east and west Scotland". Forensic Science International. 257: 203–208. doi:10.1016/j.forsciint.2015.08.008. PMID   26375622.
  18. ↑ "Order Amending Schedule III to the Controlled Drugs and Substances Act (Methylphenidate)". Canada Gazette. Government of Canada, Public Works and Government Services Canada, Public Services and Procurement Canada, Integrated Services Branch, Canada. 2017-04-05.
  19. ↑ "BTMG - Einzelnorm". Archived from the original on 2013-10-16. Retrieved 2014-02-08.
  20. ↑ "Retsinformation". Retsinformation.dk. Retrieved 30 January 2022.
  21. ↑ "Ustawa z dnia 24 kwietnia 2015 r. o zmianie ustawy o przeciwdziałaniu narkomanii oraz niektórych innych ustaw". Isap.sejm.gov.pl.
  22. ↑ "Vartotojui - tik saugūs ir efektyvūs vaistai! - I SĄRAŠAS". Vvkt.lt.
  23. ↑ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Archived from the original on 1 October 2015. Retrieved 1 October 2015.
  24. ↑ "FINLEX ® - Etusivu". www.finlex.fi. Archived from the original on 2023-05-16. Retrieved 2023-05-16.
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