3,4-Dichloromethylphenidate

Last updated

3,4-DCMP
3,4-dichloromethylphenidate (racemate).svg
Clinical data
Routes of
administration 		oral, insufflation, rectal
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Metabolism Primarily by the liver
Excretion Predominantly 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
Formula C14H17Cl2NO2
Molar mass 302.20 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 Yes check.svgY
  • Key:JUKMAYKVHWKRKY-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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.[ clarification needed ] It has been sold online as a designer drug. [1] [2]

Contents

Chemistry

3,4-DCMP is the 3,4-dichlorinated analogue of methylphenidate. The 3,4-dichlorination is a common modification done to most monoamine reuptake inhibitors.[ citation needed ]

Pharmacology

Pharmacodynamics

The result of the 3,4-dichlorination on 3,4-DCMP is a higher selectivity for the serotonin transporter and serotonin uptake inhibition. Serotonergic activity among phenidates is very rare, and 3,4-DCMP is one of only three compounds from this class with appreciable serotonergic activity, the other two being HDMP-28 & HDEP-28. The reason for the serotonergic 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 modifications done to increase serotonergic activity include naphthylaminopropane and 3,4-dichloroamphetamine.[ citation needed ]

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 modification done to increase affinity to DAT & NET include dichloropane and O-2390.[ citation needed ]

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 related compounds. [2]
CompoundDAT

(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-CTMP1.4 ± 0.123 ± 31,600 ± 150540 ± 11014 ± 610 ± 110.00.43
3,4-CEMP190 ± 14800 ± 1102,500 ± 4201,100 ± 904,200 ± 1,900190 ± 5046.70.24
TMP2110 ± 9110 ± 965,000 ± 4,0005,100 ± 7,000660 ± 5061 ± 146.00.77
Cocaine500 ± 65240 ± 15340 ± 40250 ± 40500 ± 90210 ± 301.00.88

Legality

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

References

  1. ↑ Wood S (10 April 2015). "Temporary Class Drug Order – legal highs' bubble to be 'burst'". Criminal Law Blog: Kingsley Napley.
  2. 1 2 3 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. 1 2 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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