(-)-2β-Carbomethoxy-3β-(4-fluorophenyl)tropane

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(-)-2β-Carbomethoxy-3β-(4-fluorophenyl)tropane
Systematic (IUPAC) name
methyl (1R,2S,3S,5S)-3-(4-fluorophenyl)-8-methyl- 8-azabicyclo[3.2.1]octane-2-carboxylate naphthalene-1,5-disulfonate
Identifiers
CAS number 50370-56-4
ATC code  ?
PubChem 105056
Chemical data
Formula C16H20FNO2 
Mol. mass 277.33 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes  ?


(-)-2-β-Carbomethoxy-3-β-(4-fluorophenyl)tropane (β-CFT, WIN 35,428) is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is structurally derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies. While the naphthalenedisulfonate salt is the most commonly used form in scientific research due to its high solubility in water, the free base and hydrochloride salts are known compounds and can also be produced.

Chemical Properties

CAS number: 50370-56-4 or 77210-32-3

Molecular Formula: C16H20FNO2.C10H8S2O6

IUPAC name: (CFT free base): (1R,2S,3S,5S)-3-(4-fluorophenyl)-8-methyl-8-Azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester

SMILES: CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=C(C=C3)F)C(=O)OC

Molecular weight: 277.33 (free base); 565.55 (anhydrous naphthalenedisulfonate)

Melting Point: 202-204°C

Optical Rotation: [α]D = -62.5°

Uses

CFT was discovered in 1979 during research into the mechanism of action of cocaine. A wide variety of similar tropane derivatives are also known, such as CPT (the analogue with an unsubsituted phenyl ring, CAS# 50372-80-0) and RTI-55 (another analogue with an iodine atom instead of fluorine at the 4-position of the phenyl ring, CAS# 135416-43-2), and various N-alkylated derivatives, many of which are even more potent than CFT; however the most widely used compound in scientific research has been CFT itself.

Radiolabelled forms of CFT have been used in humans and animals to map the distribution of dopamine transporters in the brain. CFT was found to be particularly useful for this application as a normal fluorine atom can be substituted with the radioactive isotope 18F which is widely used in Positron emission tomography. Another radioisotope-substituted analogue [11C]WIN-35,428 (where the carbon atom of either the N-methyl group, or the methyl from the 2-carbomethoxy group of CFT, has been replaced with 11C) is now more commonly used for this application, as it is quicker and easier in practice to make radiolabelled CFT by methylating nor-CFT or 2-desmethyl-CFT than by reacting methylecgonidine with parafluorophenylmagnesium bromide, and also avoids the requirement for a licence to work with the restricted precursor ecgonine.

CFT is about as addictive as cocaine in animal studies, but is taken less often due to its longer duration of action. Potentially this could make it a suitable drug to be used as a substitute for cocaine, in a similar manner to how methadone is used as a substitute for opiates in treating addiction.

Legal Status

CFT has no history of abuse in humans, but according to the chemical supplier Sigma-Aldrich it is illegal in the USA (Schedule II) and Germany (Kontrollierte Droge) 1, presumably due to its similar effects to cocaine; however CFT is not specifically listed as a Schedule II drug on the DEA website 2 or on the German controlled drug schedule 3 and so it is unclear on what basis Sigma-Aldrich has derived this legal information. While CFT might well be considered a controlled substance analogue in these countries there has never been any formal announcement by either the US or German government of CFT being added to the controlled substances list.

CFT might possibly also be considered a controlled substance analogue of cocaine in Canada, New Zealand and Australia, due to its related chemical structure to cocaine. According to analog law one must consider structural similarity, and CFT might well not be considered substantially similar to cocaine, having been derived by the removal of an ester linkage rather than by simply substituting extra groups onto cocaine, although a para-fluoro group has also been added to CFT. Also the intent of the user must be considered as well, so CFT would probably not be considered illegal when it is being used solely for scientific research. The relatively complex synthesis of CFT, as well as the fact that the main synthetic routes proceed via the restricted intermediate compound ecgonine, make it fairly unlikely that CFT will appear on the recreational market as a drug of abuse.

Toxicity

Sigma-Aldrich categorizes CFT as being a "very toxic" chemical and recommends the use of gloves, goggles, protective apron and respirator while handling it, and states it must only be used in a fume hood. However this description is not supported by the known toxicology of CFT based on its widespread use in animals over a 30 year period and so this extreme caution is difficult to reconcile with the chemical and pharmacological properties of the drug; this may instead reflect concerns about its abuse potential rather than actual potential to cause poisoning. The drug data sheet notes that serious side effects can occur following exposure to CFT, including CNS stimulation, dilation of eye pupils, euphoria, breathing difficulties, nervousness, restlessness, hypertension, fainting, paleness, arrhythmia, cardiac arrest, convulsions, and death. Prolonged or repeated exposure to CFT may result in habituation or addiction.

Synthesis

[1]

References

  • D'Mello GD, Goldberg DM, Goldberg SR, Stolerman IP. Conditioned taste aversion and operant behaviour in rats: effects of cocaine and a cocaine analogue (WIN 35,428). Neuropharmacology. 1979 Dec;18(12):1009-10.
  • Reith, MEA., Sershen H, Lajtha A. Saturable (3H)cocaine binding in central nervous system of mouse. Life Sciences. 1980 Sep 22;27(12):1055-62.
  • Spealman RD, Bergman J, Madras BK. Self-administration of the high-affinity cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane. Pharmacology Biochemistry and Behaviour. 1991 Aug;39(4):1011-3.
  • Milius RA, Saha JK, Madras BK, Neumeyer JL. Synthesis and Receptor Binding of N-Substituted Tropane Derivatives. High- Affinity Ligands for the Cocaine Receptor. Journal of Medicinal Chemistry. 1991,34, 1728-1731
  • Cline EJ, Scheffel U, Boja JW, Carroll FI, Katz JL, Kuhar MJ. Behavioral effects of novel cocaine analogs: a comparison with in vivo receptor binding potency. Journal of Pharmacology and Experimental Therapeutics. 1992 Mar;260(3):1174-9.
  • Singh S. Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Chemistry Reviews, 2000. 100(3): 925-1024
  • Li SM, Campbell BL, Katz JL. Interactions of cocaine with dopamine uptake inhibitors or dopamine releasers in rats discriminating cocaine. Journal of Pharmacology and Experimental Therapeutics. 2006 Jun;317(3):1088-96.



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