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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 dichlorinated at the meta- and para- positions on the phenyl ring. The 3,4-dichlorination is a common modification done to most monoamine reuptake inhibitors.

Pharmacology

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Pharmacodynamics

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The result of the 3,4-dichlorination on 3,4-DCMP is a higher selectivity 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. Examples of compounds with the same SAR modifictions done to increase serotoninergic activity include naphthylaminopropane and 3,4-dichloroamphetamine.

The 3,4-dichloro group also increases resistance to metabolism, which can be seen on the compound's greatly increased duration of action and biological half-life. Furthermore, it also results in a greatly increased affinity for both the dopamine and noradrenaline transporters, because the 3,4-dichloro group more closely mimics the 3,4-dihydroxy group found on dopamine and adrenaline. Examples of compounds with the same SAR modifiction done to increase affinity to DAT & NET include dichloropane and O-2390.

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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