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]
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]
^ abcFroimowitz 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. PMID17228864.
^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. PMID8632426.
^ abSchweri 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. PMID11961053.
^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. PMID17489581.
^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. PMID10037500.
^"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.
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