Troparil

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Troparil
WIN 35,065-2.svg
Systematic (IUPAC) name
Methyl (1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate
Clinical data
Legal status ?
Identifiers
CAS number 74163-84-1 YesY
ATC code None
PubChem CID 170832
ChEMBL CHEMBL298684 N
Chemical data
Formula C16H21NO2 
Mol. mass 259.343 g/mol
Physical data
Melt. point 190–191 °C (374–376 °F)
 N (what is this?)  (verify)

Troparil (also known as (–)-2β-Carbomethoxy-3β-phenyltropane, WIN 35,065-2, or β-CPT) is a stimulant drug used in scientific research. Troparil 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 troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine.[3] The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

Background[edit]

The first known published synthesis of troparil 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.[citation needed]

Application[edit]

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

Troparil is used in scientific research into the dopamine reuptake transporter. 3H-radiolabelled forms of troparil 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.

Troparil 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 troparil are available only in very small quantities for a very high price.

Legality[edit]

The legal status of troparil is unclear, but it may be considered a controlled substance analogue of cocaine in the United States on the grounds of its related chemical structure.

See also[edit]

References[edit]

  1. ^ Runyon, S. P.; Carroll, F. I. (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, F. I.; Kotian, P.; Dehghani, A.; Gray, J. L.; Kuzemko, M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. (1995). "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". Journal of Medical Chemistry 38 (2): 379–388. doi:10.1021/jm00002a020. PMID 7830281.  edit
  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 Medical 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.  edit
  8. ^ Ritz M.C. et al. (1990). "[3H]WIN 35,065-2: a ligand for cocaine receptors in striatum". J. Neurochem. 55 (5): 1556–1562. doi:10.1111/j.1471-4159.1990.tb04938.x. PMID 2120386. 
  9. ^ Scheffel U. et al. (1989). "Cocaine receptors: In Vivo Labelling with 3H-(-) cocaine, 3H-WIN 35,065-2, and 3H-WIN 35,428". Synapse 4 (4): 390–392. doi:10.1002/syn.890040415. PMID 2603151. 
  10. ^ Zakusov VV, Naumova BI (1985). "Pharmacology of troparil". Farmakologiia i Toksikologiia 48 (1): 15–19. PMID 3838516. 
  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 (1996). "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 33 (6): 2037–2039. doi:10.1002/jhet.5570330676. 
  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