4-Fluoromethylphenidate

4-Fluoromethylphenidate
Legal status
Legal status	CA: Schedule III; DE: NpSG (Industrial and scientific use only); UK: Under Psychoactive Substances Act;
Identifiers
	IUPAC name Methyl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate;
CAS Number	1354631-33-6 ;
PubChem CID	70876096;
ChemSpider	26350585 ;
UNII	TN2LV2C0X9;
Chemical and physical data
Formula	C14H18FNO2
Molar mass	251.301 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	222.0 °C (431.6 °F)
	SMILES FC1=CC=C(C=C1)C(C(=O)OC)C2CCCCN2;
	InChI InChI=1S/C14H18FNO2/c1-18-14(17)13(12-4-2-3-9-16-12)10-5-7-11(15)8-6-10/h5-8,12-13,16H,2-4,9H2,1H3; Key:XISBAJBPDVRSPG-UHFFFAOYSA-N;

4-Fluoromethylphenidate (also known as 4-FMPH and 4F-MPH) is a stimulant drug that acts as a higher potency dopamine reuptake inhibitor than the closely related methylphenidate.^[2]^[3]^[4]

4-Fluoromethylphenidate was studied further along with other analogues of (±)-threo-methylphenidate (TMP) to assess their potential as anti-cocaine medications. 4F-MPH was reported as having an ED₅₀ mg/kg of 0.26 (0.18–0.36), regarding its efficacy as a substitute for cocaine, and a relative potency of 3.33 compared to methylphenidate for the same purpose. This is based on its binding strength to the dopamine transporter vs. its activity as a dopamine reuptake inhibitor. In theory, this would block some of the effects of cocaine, without being as addictive.^[5] This has been misinterpreted as a dopamine vs. norepinephrine selectivity ratio.

Another study found that in the threo-isomers of methylphenidate, the meta- and para-substituted compounds with electron-withdrawing substituents tended to have increased binding potency. Compounds containing fluorine, chlorine, bromine and methyl groups were reported to be more potent than methylphenidate as well as the closely related compound 4F-EPH. 4F-MPH was reported as having the following values: [³H]WIN 35428 binding of 35.0 ± 3.0 (2) and [³H]dopamine 142 ± 2.0 (2).^[6]

Legal status

4-Fluoromethylphenidate is a Schedule I controlled substance in the US state Alabama.^[7] As of 5 May 2017, 4-fluoromethylphenidate is a controlled substance in Canada.^[8]

References

^ "The Drug Enforcement Administration's Special Testing and Research Laboratory Monograph" (PDF). February 2017.
^ 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. PMID 15026075.
^ Misra M, Shi Q, Ye X, Gruszecka-Kowalik E, Bu W, Liu Z, et al. (October 2010). "Quantitative structure-activity relationship studies of threo-methylphenidate analogs". Bioorganic & Medicinal Chemistry. 18 (20): 7221–38. doi:10.1016/j.bmc.2010.08.034. PMID 20846865.
^ Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.
^ 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. PMID 11961053.
^ 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. PMID 8632426.
^ "Alabama Senate Bill 333 - Controlled substances, Schedule I, additional synthetic controlled substances and analogue substances included in, trafficking in controlled substance analogues, requisite weight increased, Secs. 13A-12-231, 20-2-23 am'd". March 2014. Retrieved 28 September 2015.
^ "Regulations Amending the Food and Drug Regulations (Part G — Methylphenidate)". Health Canada. Government of Canada. April 5, 2017.

[1] "The Drug Enforcement Administration's Special Testing and Research Laboratory Monograph" (PDF). February 2017.

[2] 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. PMID 15026075.

[3] Misra M, Shi Q, Ye X, Gruszecka-Kowalik E, Bu W, Liu Z, et al. (October 2010). "Quantitative structure-activity relationship studies of threo-methylphenidate analogs". Bioorganic & Medicinal Chemistry. 18 (20): 7221–38. doi:10.1016/j.bmc.2010.08.034. PMID 20846865.

[4] Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.

[5] 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. PMID 11961053.

[6] 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. PMID 8632426.

[7] "Alabama Senate Bill 333 - Controlled substances, Schedule I, additional synthetic controlled substances and analogue substances included in, trafficking in controlled substance analogues, requisite weight increased, Secs. 13A-12-231, 20-2-23 am'd". March 2014. Retrieved 28 September 2015.

[8] "Regulations Amending the Food and Drug Regulations (Part G — Methylphenidate)". Health Canada. Government of Canada. April 5, 2017.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

Legal status

See also

References