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]
 | |
| Clinical data | |
|---|---|
| Routes of administration | oral, insufflation, rectal |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Metabolism | Primarily by the liver |
| Excretion | Predominantly renal |
| Identifiers | |
| |
| 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) | |
| |
| |
  (what is this?) (verify) | |
Chemistry
edit3,4-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
editPharmacodynamics
editThe 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]
| 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
editAs 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
editReferences
edit- ^ Wood S (10 April 2015). "Temporary Class Drug Order – legal highs' bubble to be 'burst'". Criminal Law Blog: Kingsley Napley.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "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.
- ^ 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". Retrieved 29 June 2015.