Troparil

Troparil

Systematic (IUPAC) name
methyl (1R,2S,3S,5S)-8-methyl-3-phenyl -8-azabicyclo[3.2.1]octane-2-carboxylate
Clinical data
Pregnancy cat.	?
Legal status	? (UK)
Identifiers
CAS number	74163-84-1 Y
ATC code	None
PubChem	CID 170832
ChEMBL	CHEMBL607100 N
Chemical data
Formula	C16H21NO2
Mol. mass	259.343 g/mol
SMILES	eMolecules & PubChem
Physical data
Melt. point	190–191 °C (374–376 °F)
N(what is this?)  (verify)

(–)-2β-Carbomethoxy-3β-phenyltropane (Troparil, WIN 35,065-2, β-CPT) is a stimulant drug used in scientific research. CPT is a phenyltropane based dopamine reuptake inhibitor (DRI) and is derived from methylecgonidine. Troparil is documented to be a few times more potent than cocaine as a dopamine reuptake inhibitor,^[1] but is less potent as a serotonin reuptake inhibitor,^[2] and has a duration spanning a few times longer, since the phenyl ring is directly connected to tropane through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so CPT is a pure stimulant. This change in activity also makes CPT slightly less cardiotoxic than cocaine.^[3] The most commonly used form of β-CPT is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

Background

The first known published synthesis of WIN 35,065-2 and WIN 35,428 is by Clarke and co-workers during the 1970s.^[4][5] Apparently it was their intention to separate the stimulant actions of cocaine from its toxicity and dependence liability. Troparil is the only regular phenyltropane having a NET affinity that exceeds the DAT affinity.

Application & Uses

Phenyltropanes are likely to have less abuse and dependency compared with cocaine.^[6][7]

CPT is used in scientific research into the dopamine reuptake transporter. ³H-radiolabelled forms of CPT have been used in humans and animals to map the distribution of dopamine transporters in the brain.^[8][9] It is also used for animal research into stimulant drugs as an alternative to cocaine which produces similar effects,^[10] but avoids the stringent licensing requirements for the use of cocaine itself.

β-CPT has similar effects to cocaine in animal studies,^[11][12] but recreational use of this compound to date has proven extremely rare. Despite being easily made by the reaction of methylecgonidine with phenylmagnesium bromide,^[5][13] the relative scarcity of methylecgonidine and the demanding reaction conditions required for the synthesis^[14][15] put production of this compound beyond the capacity of most illicit drug manufacturers, and legitimate supplies of β-CPT are available only in very small quantities for a very high price.

Legality

The legal status of CPT is unclear. Sigma-Aldrich claims that it is a Schedule II / Class B drug in the USA and UK,^[16] but it is not listed in any controlled drugs legislation or published lists of illegal drugs from the relevant government departments in these jurisdictions. Nevertheless, CPT may be considered a controlled substance analogue of cocaine on the grounds of its related chemical structure in some jurisdictions such as Australia and New Zealand.

This is somewhat unclear as there has not been any legal precedent set to determine whether a compound derived by the simplification of an illegal drug molecule (removal of an ester link in this instance) can be considered "substantially similar" to the illegal drug; all previous examples of designer drugs such as α-methylfentanyl have been derived instead by adding extra substituent groups onto the molecule, and the laws covering this area only refer to the addition or substitution of groups onto the illegal drug molecule, not their removal. An excessively broad precedent set in this area would be extremely problematic from a legal standpoint.

See also

• WIN 35,428
• List of cocaine analogues
• WIN 25,978

References

1. ^ Runyon, S. P.; Carroll (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Current Topics in Medicinal Chemistry 6 (17): 1825–1843. doi:10.2174/156802606778249775. ISSN 1568-0266. PMID 17017960.  edit
2. ^ Carroll FI, Kotian P, Dehghani A, Gray JL, Kuzemko MA, Parham KA, Abraham P, Lewin AH, Boja JW, Kuhar MJ. Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter. J Med Chem. 1995 Jan 20;38(2):379-88. PMID 7830281
3. ^ Phillips, K.; Luk, A.; Soor, G.; Abraham, J.; Leong, S.; Butany, J. (2009). "Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options". American journal of cardiovascular drugs : drugs, devices, and other interventions 9 (3): 177–196. doi:10.2165/00129784-200909030-00005. PMID 19463023.  edit
4. ^ U.S. Patent 3,813,404
5. ^ ^{a b} Clarke, R. L.; Daum, S. J.; Gambino, A. J.; Aceto, M. D.; Pearl, J.; Levitt, M.; Cumiskey, W. R.; Bogado, E. F. (1973). "Compounds affecting the central nervous system. 4. 3 Beta-phenyltropane-2-carboxylic esters and analogs". Journal of medicinal chemistry 16 (11): 1260–1267. doi:10.1021/jm00269a600. PMID 4747968.  edit
6. ^ Wee, S.; Carroll, F.; Woolverton, W. (2006). "A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants". Neuropsychopharmacology 31 (2): 351–362. doi:10.1038/sj.npp.1300795. PMID 15957006.  edit
7. ^ Kimmel, H. .; O'Connor, J. .; Carroll, F. .; Howell, L. . (2007). "Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys". Pharmacology, biochemistry, and behavior 86 (1): 45–54. doi:10.1016/j.pbb.2006.12.006. PMC 1850383. PMID 17258302. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1850383.  edit
8. ^ Ritz M.C. et al. [3H]WIN 35,065-2: a ligand for cocaine receptors in striatum. J. Neurochem. 1990, 55, 1556-1562.
9. ^ Scheffel U. et al. Cocaine receptors: In Vivo Labelling with 3H-(-) cocaine, 3H-WIN 35,065-2, and 3H-WIN 35,428. Synapse 1989, 4, 390-392.
10. ^ Zakusov VV, Naumova BI. Pharmacology of troparil. Farmakologiia i Toksikologiia. 1985 Jan-Feb;48(1):15-9.
11. ^ Balster, R. L.; Carroll, F. I.; Graham, J. H.; Mansbach, R. S.; Rahman, M. A.; Philip, A.; Lewin, A. H.; Showalter, V. M. (1991). "Potent substituted-3 beta-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects". Drug and alcohol dependence 29 (2): 145–151. doi:10.1016/0376-8716(91)90043-X. PMID 1797525.  edit
12. ^ Xu, L.; Kelkar, S.; Lomenzo, S.; Izenwasser, S.; Katz, J.; Kline, R.; Trudell, M. (1997). "Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives". Journal of Medicinal Chemistry 40 (6): 858–863. doi:10.1021/jm960739c. PMID 9083474.  edit
13. ^ Kline Rh, J.; Wright, J.; Fox, K. M.; Eldefrawi, M. E. (1990). "Synthesis of 3-arylecgonine analogues as inhibitors of cocaine binding and dopamine uptake". Journal of Medicinal Chemistry 33 (7): 2024–2027. doi:10.1021/jm00169a036. PMID 2362282.  edit
14. ^ Xu L, Trudell ML. Stereoselective Synthesis of 2β-Carbomethoxy-3β-Phenyltropane Derivatives. Enhanced Stereoselectivity Observed for the Conjugate Addition Reaction of Phenylmagnesium Bromide Derivatives with Anhydro Dichloromethane. Journal of Heterocyclic Chemistry. 1996; 33(6): 2037-2039.
15. ^ Milius, R. A.; Saha, J. K.; Madras, B. K.; Neumeyer, J. L. (1991). "Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor". Journal of Medicinal Chemistry 34 (5): 1728–1731. doi:10.1021/jm00109a029. PMID 2033595.  edit
16. ^ Sigma-Aldrich pharmaceutical page for Troparil/CPT