threo-4-Methylmethylphenidate (4-MeTMP) is a stimulant drug related to methylphenidate. It is slightly less potent than methylphenidate and has relatively low efficacy at blocking dopaminereuptake despite its high binding affinity, which led to its investigation as a possible substitute drug for treatment of stimulant abuse (cf. nocaine).[1] On the other hand, several other simple ring-substituted derivatives of threo-methylphenidate such as the 4-fluoro and 3-chloro compounds are more potent than methylphenidate both in efficacy as dopamine reuptake inhibitors and in animal drug discrimination assays.[2][3][4]
In the United States, 4-methylmethylphenidate may be considered illegal if intended for human consumption under the federal analogue act as a structural analog of methylphenidate.
In the United States, on September 22, 2023, the DEA filed a proposed rule for placement of ethylphenidate into Schedule I status, which would include its isomers. 4-Methylmethylphenidate is a positional isomer of ethylphenidate and thus the scheduling of ethylphenidate into Schedule I status would cause 4-methylmethylphenidate to be a Schedule I substance as well.[8]
^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): 1201–9. doi:10.1021/jm950697c. PMID8632426.
^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): 527–35. doi:10.1124/jpet.301.2.527. PMID11961053.
^Davies HM, Hopper DW, Hansen T, Liu Q, Childers SR (April 2004). "Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites". Bioorganic & Medicinal Chemistry Letters. 14 (7): 1799–802. doi:10.1016/j.bmcl.2003.12.097. PMID15026075.
