3,4-Dichloromethylphenidate Explained

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]

Chemistry

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

Pharmacodynamics

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]} However, H. M. Deutsch's discrimination ratio implies it to be more reinforcing than cocaine.

Inhibition of [¹²⁵I]RTI-55 Binding and [³H]Monoamine Uptake of 3,4-DCMP diastereomers, and releated compounds.^[7] !Compound!DAT (Ki, nM)!DA uptake IC50 (nM)!SERT (Ki, nM)!5HT uptakeIC50 (nM)!NET (Ki, nM)!NE uptakeIC50 (nM)!NET/DATselectivity!NE/DA uptakeselectivity

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

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

• 3-Bromomethylphenidate
• 4-Methylmethylphenidate
• Cilobamine
• Dichloropane
• HDEP-28
• HDMP-28
• Isopropylphenidate
• LR-5182
• O-2390
• Propylphenidate

Notes and References

1. Web site: Wood S . 10 April 2015 . Temporary Class Drug Order – legal highs' bubble to be 'burst' . Criminal Law Blog: Kingsley Napley.
2. Wayment HK, Deutsch H, Schweri MM, Schenk JO . Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? . Journal of Neurochemistry . 72 . 3 . 1266–1274 . March 1999 . 10037500 . 10.1046/j.1471-4159.1999.0721266.x . 26220081 . free .
3. Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM . 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 . March 1996 . 8632426 . 10.1021/jm950697c .
4. Schweri MM, Deutsch HM, Massey AT, Holtzman SG . Biochemical and behavioral characterization of novel methylphenidate analogs . The Journal of Pharmacology and Experimental Therapeutics . 301 . 2 . 527–535 . May 2002 . 11961053 . 10.1124/jpet.301.2.527 .
5. Kim DI, Deutsch HM, Ye X, Schweri MM . Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate . Journal of Medicinal Chemistry . 50 . 11 . 2718–2731 . May 2007 . 17489581 . 10.1021/jm061354p .
6. Wayment HK, Deutsch H, Schweri MM, Schenk JO . Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? . Journal of Neurochemistry . 72 . 3 . 1266–1274 . March 1999 . 10037500 . 10.1046/j.1471-4159.1999.0721266.x .
7. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A . Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter . Journal of Medicinal Chemistry . 50 . 2 . 219–232 . January 2007 . 17228864 . 10.1021/jm0608614 .
8. Web site: 关于印发《非药用类麻醉药品和精神药品列管办法》的通知 . China Food and Drug Administration . 27 September 2015 . zh . 1 October 2015 . https://web.archive.org/web/20151001222554/http://www.sfda.gov.cn/WS01/CL0056/130753.html . 1 October 2015 . dead .
9. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/420983/TCDO_methylphenidate_NPS.pdf Methylphenidate-based NPS: A review of the evidence of use and harm. Advisory Council on the Misuse of Drugs, 31 March 2015
10. Web site: Cannabinoider föreslås bli klassade som hälsofarlig vara . 29 June 2015.