Dimethocaine

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Dimethocaine
Dimethocaine-structure.svg
Clinical data
Other namesDMC, larocaine
ATC code
  • none
Legal status
Legal status
Identifiers
  • (3-diethylamino-2,2-dimethylpropyl)-4-aminobenzoate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H26N2O2
Molar mass 278.396 g·mol−1
3D model (JSmol)
Density 1.0±0.1 g/cm3 (predicted)
Melting point 48 to 51 °C (118 to 124 °F) (experimental)
Boiling point 334 to 403 °C (633 to 757 °F) at 760 mmHg
  • NC1=CC=C(C(OCC(C)(C)CN(CC)CC)=O)C=C1
  • InChI=1S/C16H26N2O2/c1-5-18(6-2)11-16(3,4)12-20-15(19)13-7-9-14(17)10-8-13/h7-10H,5-6,11-12,17H2,1-4H3 X mark.svgN
  • Key:OWQIUQKMMPDHQQ-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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”. [1] The structure of dimethocaine, being a 4-aminobenzoic acid ester, resembles that of procaine. It is found as a white powder at room temperature. [2]

Contents

When a product sold online in the UK in June 2010, advertised as dimethocaine was tested, it was found to be a mixture of caffeine and lidocaine, [3] and the lack of any dopaminergic stimulant ingredient in such mixes may explain the limited recreational effects reported by many users. Other samples tested have however been shown to contain genuine dimethocaine, and one branded "bath salt" product containing primarily dimethocaine as the active ingredient, was noted to have been particularly subject to abuse by intravenous drug users in Ireland. [4]

History

Dimethocaine was originally synthesized by the Hoffmann-La Roche company in 1930. It was sold under the market name larocaine. During the 1930s dimethocaine gained popularity in the US as a local anesthetic. Just like cocaine and procaine, it was used during surgery, primarily in dentistry, ophthalmology and otolaryngology. However, in the 1940s, it was removed from the market because of its psychoactive effects and risk of addiction. Nowadays dimethocaine is abused for these psychoactive effects. It is sold as a cocaine surrogate to circumvent legislation issues. [1] [5] [6]

Pharmacology

Pharmacodynamics

Dimethocaine and structurally related local anesthetics such as cocaine and procaine inhibit the uptake of dopamine (DA) by blocking dopamine transporters (DAT). [7] The dopamine transporter controls the dynamics of the neurotransmitter dopamine. This neurotransmitter controls many functions including movement, cognition and mood. Drugs such as cocaine and dimethocaine induce dopamine overflow by inhibiting dopamine transporters and thus creating a euphoric effect. [8] In addition to inhibiting dopamine uptake, dimethocaine was also shown to inhibit the binding of CFT, a different dopamine uptake inhibitor. [7] These inhibitory properties are responsible for the stimulatory effects of dimethocaine on the central nervous system. [5] Both in vivo and in vitro measurements of dopamine transporter activity showed that dimethocaine is a potent and efficacious dopaminergic reuptake inhibitor (also called a dopamine indirect agonist). [7] These effects were mainly observed in the nucleus accumbens, a region in the basal forebrain. [5] Comparison of the pharmacological potencies of different local anesthetics revealed the following potency order: [5]

cocaine > dimethocaine > tetracaine > procaine > chloroprocaine

Furthermore, the administration of dimethocaine has been shown to lead to antinociceptive responses at nontoxic doses in mice. [9] These responses are suggested to be at least partially caused by the effects of dimethocaine on the central nervous system. A memory impairing effect observed in mice after administration of dimethocaine has been proposed to be a result of a non-anesthetic mechanism of action. [10]

Pharmacokinetics

When inhaled, dimethocaine starts working in 10–30 minutes, with highest effects at 60–120 minutes and until 4–6 hours there is a period of action with the ‘after-effects’. [11] The after effects include fatigue and slight mental impairment. [6]

Metabolism

The exact metabolic pathways of dimethocaine have not been researched, but the different metabolites have been examined in Wistar rats. After administration of dimethocaine, different metabolites have been found and identified in their urine. Due to these metabolites, different metabolic pathways could have been postulated. The main phase I reactions are ester hydrolysis, deethylation, hydroxylation of the aromatic system, or a combination of these three. [1] The main phase II reactions are N-acetylation, glucuronidation and a combination of both. [5] [1] Different cytochrome P450 isozymes are involved in the initial steps of human metabolism. The N-acetylation is catalyzed by the NAT2 isozyme. [12]

Efficacy and side effects

Just like cocaine, dimethocaine inhibits the uptake of dopamine in the brain by interfering with the dopamine transporters. [13] The potency of these drugs is linked to their affinity for the dopamine transporters, and their potency to inhibit dopamine uptake. [7]

In studies with rhesus monkeys the affinity of dimethocaine for dopamine transporters is smaller than that of cocaine, whereas dimethocaine's potency to inhibit dopamine uptake is similar. This means that more of dimethocaine is needed to reach a similar response. The peak effects occurred within 10 to 20 minutes after the injection and decreased to baseline levels within an hour. [13]

Dimethocaine is often abused as a legal substitute for cocaine. The drug is administered intravenously or nasally, because ingestion would lead to rapid hydrolyzation. [5] Its positive effects are euphoria, stimulation, increased talkativeness and mood lift. [6] However, because the drug acts similar as cocaine, it has comparable negative side effects. These side effects include: tachycardia, difficulty with breathing, pain on the chest, vasoconstriction, insomnia, paranoia and anxiety. [6] Dimethocaine probably poses larger health issues than cocaine. This is due to the fact that more dimethocaine must be administered to produce the same euphoric feeling, resulting in larger risk for the negative effects.

Toxicity

Humans

Cocaine and other local anesthetics are known to produce cardiotoxicity by blocking sodium channels. However, no reports have been published of these same effects of cardiotoxicity associated with dimethocaine. [2] There has been little research about toxicity of dimethocaine in humans, and therefore the exact lethal or pharmacological doses are unknown.

Animals

For mice, the dose at which acute toxicity occurs for intravenous administration is 40 mg/kg and for subcutaneous injection (injection in the layer of skin directly below the dermis and epidermis) this is 380 mg/kg. [14] The lethal dose of dimethocaine for a mouse is 0.3 g per kilogram body weight. [15]

An abdominal constriction test was performed in mice, using doses of 5, 10, and 20 mg/kg of dimethocaine which were administered subcutaneously. This test showed induced dose-dependent antinociceptive responses, which are processes that block detection of a painful or injurious stimulus by sensory neurons. [9]

Impairment of memory processes was found to be a toxic effect in the elevated plus-maze test in mice. [10]

Sweden's public health agency suggested classifying Dimethocaine as a hazardous substance, on September 25, 2019. [16]

See also

Related Research Articles

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">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">WIN-35428</span> Chemical compound

(–)-2-β-Carbomethoxy-3-β-(4-fluorophenyl)tropane 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">Vanoxerine</span> Chemical compound

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, but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects. Vanoxerine has also been observed to be a potent blocker of the IKr (hERG) channel. Vanoxerine also binds with nanomolar affinity to the serotonin transporter.

<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">(+)-CPCA</span> Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<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">Ethylphenidate</span> Stimulant analog of methylphenidate

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

<span class="mw-page-title-main">RTI-121</span> Chemical compound

(–)-2β-Carboisopropoxy-3β-(4-iodophenyl)tropane is a stimulant drug used in scientific research, which was developed in the early 1990s. RTI-121 is a phenyltropane based, highly selective dopamine reuptake inhibitor and is derived from methylecgonidine. RTI-121 is a potent and long-lasting stimulant, producing stimulant effects for more than 10 hours after a single dose in mice which would limit its potential uses in humans, as it might have significant abuse potential if used outside a medical setting. However RTI-121 occupies the dopamine transporter more slowly than cocaine, and so might have lower abuse potential than cocaine itself.

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

Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects.

<span class="mw-page-title-main">RTI-126</span> Pharmaceutical drug

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<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">Amfonelic acid</span> Chemical compound

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<span class="mw-page-title-main">RTI-113</span> Chemical compound

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<span class="mw-page-title-main">RTI-112</span> Chemical compound

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

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<span class="mw-page-title-main">PNU-99,194</span> Chemical compound

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References

  1. 1 2 3 4 Meyer MR, Lindauer C, Welter J, Maurer HH (March 2014). "Dimethocaine, a synthetic cocaine analogue: studies on its in-vivo metabolism and its detectability in urine by means of a rat model and liquid chromatography-linear ion-trap (high-resolution) mass spectrometry". Analytical and Bioanalytical Chemistry. 406 (7): 1845–54. doi:10.1007/s00216-013-7539-0. PMID   24448968. S2CID   10850370.
  2. 1 2 Dargan P, Wood D (2013-08-06). Novel Psychoactive Substances: Classification, Pharmacology and Toxicology. Amsterdam: Elsevier/Academic Press. ISBN   978-0-12-415911-2.
  3. ↑ Brandt SD, Sumnall HR, Measham F, Cole J (July 2010). "Second generation mephedrone. The confusing case of NRG-1". BMJ. 341: c3564. doi:10.1136/bmj.c3564. PMID   20605894. S2CID   20354123.
  4. ↑ An overview of new psychoactive substances and the outlets supplying them Archived November 25, 2011, at the Wayback Machine
  5. 1 2 3 4 5 6 Lindauer C (2014). Toxicokinetics of Emerging Drugs of Abuse: In vivo and in vitro studies on the metabolic fate of the cocaine-derived designer drug dimethocaine. Homburg/Saar: University of Saarland.
  6. 1 2 3 4 "Dimethocaine - The Drug Classroom". The Drug Classroom. Retrieved 2018-03-16.
  7. 1 2 3 4 Woodward JJ, Compton DM, Balster RL, Martin BR (April 1995). "In vitro and in vivo effects of cocaine and selected local anesthetics on the dopamine transporter". European Journal of Pharmacology. 277 (1): 7–13. doi:10.1016/0014-2999(95)00042-J. PMID   7635175.
  8. ↑ Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and disease states". Trends in Pharmacological Sciences. 34 (9): 489–96. doi:10.1016/j.tips.2013.07.005. PMC   3831354 . PMID   23968642.
  9. 1 2 Rigon AR, Takahashi RN (June 1996). "The effects of systemic procaine, lidocaine and dimethocaine on nociception in mice". General Pharmacology. 27 (4): 647–50. doi:10.1016/0306-3623(95)02079-9. PMID   8853299.
  10. 1 2 Blatt SL, Takahashi RN (April 1998). "Memory-impairing effects of local anesthetics in an elevated plus-maze test in mice" (PDF). Brazilian Journal of Medical and Biological Research. 31 (4): 555–9. doi: 10.1590/s0100-879x1998000400013 . PMID   9698809.
  11. ↑ Greene SL (2013). "Miscellaneous Compounds". Novel Psychoactive Substances. pp. 393–409. doi:10.1016/b978-0-12-415816-0.00017-1. ISBN   9780124158160.
  12. ↑ Meyer MR, Lindauer C, Maurer HH (February 2014). "Dimethocaine, a synthetic cocaine derivative: studies on its in vitro metabolism catalyzed by P450s and NAT2". Toxicology Letters. 225 (1): 139–46. doi:10.1016/j.toxlet.2013.11.033. PMID   24309420.
  13. 1 2 Wilcox KM, Kimmel HL, Lindsey KP, Votaw JR, Goodman MM, Howell LL (December 2005). "In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys". Synapse. 58 (4): 220–8. CiteSeerX   10.1.1.327.1264 . doi:10.1002/syn.20199. PMID   16206183. S2CID   15631376.
  14. ↑ TOKYO CHEMICAL INDUSTRY CO., LTD. (2012-09-28). "Material Safety Data Sheet Dimethocaine".
  15. ↑ Mayer LL (1935). "Larocaine, a new anesthetic". Arch Ophthalmol. 14 (3): 408–411. doi:10.1001/archopht.1935.00840090094004.
  16. ↑ "Tretton ämnen föreslås klassas som narkotika eller hälsofarlig vara" (in Swedish). Folkhälsomyndigheten. 25 September 2019. Archived from the original on 31 October 2019. Retrieved 11 November 2019.
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