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3,4-Dichloromethylphenidate

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3,4-DCMP
Clinical data
Routes of
administration		oral, insufflation, rectal
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
MetabolismPrimarily by the liver
ExcretionPredominantly renal
Identifiers
  • Methyl 2-(3,4-dichlorophenyl)-2-(piperidin-2-yl)acetate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H17Cl2NO2
Molar mass302.20 g·mol−1
3D model (JSmol)
  • COC(=O)C(c1ccc(c(c1)Cl)Cl)C2CCCCN2
  • InChI=1S/C14H17Cl2NO2/c1-19-14(18)13(12-4-2-3-7-17-12)9-5-6-10(15)11(16)8-9/h5-6,8,12-13,17H,2-4,7H2,1H3 checkY
  • Key:JUKMAYKVHWKRKY-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

3,4-dichloromethylphenidate (abbreviated as 3,4-DCMP, and incorrectly as 3,4-CTMP for the d,l-threo diastereomer) 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.[1][2]

Chemistry

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3,4-DCMP is an analogue of methylphenidate which was chlorinated at the meta- and para- positions on the phenyl ring. This results in greatly increased potency, duration and affinity for the serotonin transporter and serotonin uptake inhibition. Serotoninergic activity among phenidates is very rare, and 3,4-DCMP is one of only three compounds from this class with appreciable serotoninergic activity, the other two being HDMP-28 & HDEP-28. The reason for the serotoninergic activity of all three compounds is a bulky aryl ring system (in the case of the aforementioned compounds, a 2-naphthalene ring), which mimics the bicyclic indole ring system of serotonin.

Pharmacology

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Pharmacokinetics

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3,4-DCMP most likely follows a similar metabolic fate as methylphenidate, primarily through hydrolysis of the ester bond into 3,4-dichloro-ritalinic acid, which is then primarily excreted in urine.

Pharmacodynamics

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3,4-CTMP, the d,l-threo diastereomer of 3,4-DCMP, is approximately seven times more potent than methylphenidate in animal studies, but has weaker reinforcing effects due to its slower onset of action.[2][3][4][5][6][7] However, H. M. Deutsch's discrimination ratio[clarification needed] implies it to be more reinforcing than cocaine.[5]

Inhibition of [125I]RTI-55 Binding and [3H]Monoamine Uptake of 3,4-DCMP diastereomers, and releated compounds.[2]
Compound DAT

(Ki, nM)

DA uptake

IC50 (nM)

SERT

(Ki, nM)

5HT uptake

IC50 (nM)

NET

(Ki, nM)

NE uptake

IC50 (nM)

NET/DAT

selectivity

NE/DA uptake

selectivity

3,4-CTMP 1.4 ± 0.1 23 ± 3 1,600 ± 150 540 ± 110 14 ± 6 10 ± 1 10.0 0.43
3,4-CEMP1 90 ± 14 800 ± 110 2,500 ± 420 1,100 ± 90 4,200 ± 1,900 190 ± 50 46.7 0.24
TMP2 110 ± 9 110 ± 9 65,000 ± 4,000 5,100 ± 7,000 660 ± 50 61 ± 14 6.0 0.77
Cocaine 500 ± 65 240 ± 15 340 ± 40 250 ± 40 500 ± 90 210 ± 30 1.0 0.88
  • 1 This is an abbreviation of the d,l-erythro diastereomer of 3,4-DCMP.
  • 2 This is an abbreviation of d,l-threomethylphenidate, more widely known by its brand name Ritalin.

Legality

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As of October 2015 3,4-CTMP is a controlled substance in China.[8]

3,4-CTMP was banned in the UK as a Temporary Class Drug from April 2015 following its unapproved sale as a designer drug.[9]

Sweden's public health agency suggested to classify 3,4-CTMP as hazardous substance on 10 November 2014.[10]

See also

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References

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  1. ^ Wood S (10 April 2015). "Temporary Class Drug Order – legal highs' bubble to be 'burst'". Criminal Law Blog: Kingsley Napley.
  2. ^ a b c Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, et al. (January 2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry. 50 (2): 219–232. doi:10.1021/jm0608614. PMID 17228864.
  3. ^ Wayment HK, Deutsch H, Schweri MM, Schenk JO (March 1999). "Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists?". Journal of Neurochemistry. 72 (3): 1266–1274. doi:10.1046/j.1471-4159.1999.0721266.x. PMID 10037500. S2CID 26220081.
  4. ^ Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM (March 1996). "Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs". Journal of Medicinal Chemistry. 39 (6): 1201–1209. doi:10.1021/jm950697c. PMID 8632426.
  5. ^ a b Schweri MM, Deutsch HM, Massey AT, Holtzman SG (May 2002). "Biochemical and behavioral characterization of novel methylphenidate analogs". The Journal of Pharmacology and Experimental Therapeutics. 301 (2): 527–535. doi:10.1124/jpet.301.2.527. PMID 11961053.
  6. ^ Kim DI, Deutsch HM, Ye X, Schweri MM (May 2007). "Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate". Journal of Medicinal Chemistry. 50 (11): 2718–2731. doi:10.1021/jm061354p. PMID 17489581.
  7. ^ Wayment HK, Deutsch H, Schweri MM, Schenk JO (March 1999). "Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists?". Journal of Neurochemistry. 72 (3): 1266–1274. doi:10.1046/j.1471-4159.1999.0721266.x. PMID 10037500.
  8. ^ "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.
  9. ^ Methylphenidate-based NPS: A review of the evidence of use and harm. Advisory Council on the Misuse of Drugs, 31 March 2015
  10. ^ "Cannabinoider föreslås bli klassade som hälsofarlig vara". Retrieved 29 June 2015.
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