Chemistry:3,4-Dichloromethylphenidate
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]
Chemistry
Pharmacology
Pharmacodynamics
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[clarification needed]. 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]
| 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
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
References
- ↑ "Temporary Class Drug Order – legal highs' bubble to be 'burst'". Criminal Law Blog: Kingsley Napley. 10 April 2015. https://www.kingsleynapley.co.uk/insights/blogs/criminal-law-blog/temporary-class-drug-order-legal-highs-bubble-to-be-burst.
- ↑ 2.0 2.1 2.2 "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. doi:10.1021/jm0608614. PMID 17228864.
- ↑ "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. doi:10.1046/j.1471-4159.1999.0721266.x. PMID 10037500.
- ↑ "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. doi:10.1021/jm950697c. PMID 8632426.
- ↑ 5.0 5.1 "Biochemical and behavioral characterization of novel methylphenidate analogs". The Journal of Pharmacology and Experimental Therapeutics 301 (2): 527–535. May 2002. doi:10.1124/jpet.301.2.527. PMID 11961053.
- ↑ "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. doi:10.1021/jm061354p. PMID 17489581.
- ↑ "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. doi:10.1046/j.1471-4159.1999.0721266.x. PMID 10037500.
- ↑ "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 zh). China Food and Drug Administration. 27 September 2015. http://www.sfda.gov.cn/WS01/CL0056/130753.html.
- ↑ Methylphenidate-based NPS: A review of the evidence of use and harm. Advisory Council on the Misuse of Drugs, 31 March 2015
- ↑ "Cannabinoider föreslås bli klassade som hälsofarlig vara". http://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2014/november/cannabinoider-foreslas-bli-klassade-som-halsofarlig-vara/.
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