Troparil
{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 447760207
| IUPAC_name = Methyl (1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate
| image = Phenyltropane 11a - WIN 35065-2 - Troparil.svg
| image_class = skin-invert-image
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 298684
| tradename =
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK = PSA
| legal_US = Schedule II
| legal_status =
| routes_of_administration =
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 74163-84-1
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 11M96D7J17
| ATC_prefix = none
| ATC_suffix =
| PubChem = 170832
| ChemSpiderID = 149355
| C = 16
| H = 21
| N = 1
| O = 2
| smiles = CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=CC=C3)C(=O)OC
| StdInChI = 1S/C16H21NO2/c1-17-12-8-9-14(17)15(16(18)19-2)13(10-12)11-6-4-3-5-7-11/h3-7,12-15H,8-10H2,1-2H3/t12-,13+,14+,15-/m0/s1
| StdInChIKey = OMBOXYLBBHNWHL-YJNKXOJESA-N
| melting_point = 190
| melting_high = 191
}}
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) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor,{{cite journal | vauthors = Runyon SP, Carroll FI | title = Dopamine transporter ligands: recent developments and therapeutic potential | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1825–43 | year = 2006 | pmid = 17017960 | doi = 10.2174/156802606778249775 }} but is less potent as a serotonin reuptake inhibitor,{{cite journal | vauthors = Carroll FI, Kotian P, Dehghani A, Gray JL, Kuzemko MA, Parham KA, Abraham P, Lewin AH, Boja JW, Kuhar MJ | display-authors = 6 | title = 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 = Journal of Medicinal Chemistry | volume = 38 | issue = 2 | pages = 379–88 | date = January 1995 | pmid = 7830281 | doi = 10.1021/jm00002a020 }} and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring 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.{{cite journal | vauthors = Phillips K, Luk A, Soor GS, Abraham JR, Leong S, Butany J | title = Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options | journal = American Journal of Cardiovascular Drugs | volume = 9 | issue = 3 | pages = 177–96 | year = 2009 | pmid = 19463023 | doi = 10.1007/bf03256574 | s2cid = 70385136 }} 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
The first known published synthesis of troparil and the related compound WIN 35428 is by Clarke and co-workers during the 1970s.{{US patent|3813404}} 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|date=June 2012}}
Application
Phenyltropanes are likely to have less abuse and dependency compared with cocaine.{{cite journal | vauthors = Wee S, Carroll FI, Woolverton WL | title = A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants | journal = Neuropsychopharmacology | volume = 31 | issue = 2 | pages = 351–62 | date = February 2006 | pmid = 15957006 | doi = 10.1038/sj.npp.1300795 | doi-access = free }}{{cite journal | vauthors = Kimmel HL, O'Connor JA, Carroll FI, Howell LL | title = Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys | journal = Pharmacology, Biochemistry, and Behavior | volume = 86 | issue = 1 | pages = 45–54 | date = January 2007 | pmid = 17258302 | pmc = 1850383 | doi = 10.1016/j.pbb.2006.12.006 }}
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.{{cite journal | vauthors = Ritz MC, Boja JW, Grigoriadis D, Zaczek R, Carroll FI, Lewis AH, Kuhar MJ | title = [3H]WIN 35,065-2: a ligand for cocaine receptors in striatum | journal = Journal of Neurochemistry | volume = 55 | issue = 5 | pages = 1556–62 | date = November 1990 | pmid = 2120386 | doi = 10.1111/j.1471-4159.1990.tb04938.x | s2cid = 32490965 | url = https://zenodo.org/record/1230647 }}{{cite journal | vauthors = Scheffel U, Boja JW, Kuhar MJ | title = Cocaine receptors: in vivo labeling with 3H-(-)cocaine, 3H-WIN 35,065-2, and 3H-WIN 35,428 | journal = Synapse | volume = 4 | issue = 4 | pages = 390–2 | year = 1989 | pmid = 2603151 | doi = 10.1002/syn.890040415 | s2cid = 43839331 | url = https://zenodo.org/record/1229373 }} It is also used for animal research into stimulant drugs as an alternative to cocaine which produces similar effects,{{cite journal | vauthors = Zakusov VV, Naumova BI | title = [Pharmacology of troparil] | journal = Farmakologiia i Toksikologiia | volume = 48 | issue = 1 | pages = 15–9 | year = 1985 | pmid = 3838516 }} but avoids the stringent licensing requirements for the use of cocaine itself.
Troparil has similar effects to cocaine in animal studies,{{cite journal | vauthors = Balster RL, Carroll FI, Graham JH, Mansbach RS, Rahman MA, Philip A, Lewin AH, Showalter VM | display-authors = 6 | title = Potent substituted-3 beta-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects | journal = Drug and Alcohol Dependence | volume = 29 | issue = 2 | pages = 145–51 | date = December 1991 | pmid = 1797525 | doi = 10.1016/0376-8716(91)90043-X }}{{cite journal | vauthors = Xu L, Kelkar SV, Lomenzo SA, Izenwasser S, Katz JL, Kline RH, Trudell ML | title = Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 6 | pages = 858–63 | date = March 1997 | pmid = 9083474 | doi = 10.1021/jm960739c }} but recreational use of this compound to date has proven extremely rare. Despite being easily made by the reaction of methylecgonidine with phenylmagnesium bromide,{{cite journal | vauthors = Clarke RL, Daum SJ, Gambino AJ, Aceto MD, Pearl J, Levitt M, Cumiskey WR, Bogado EF | display-authors = 6 | title = Compounds affecting the central nervous system. 4. 3 Beta-phenyltropane-2-carboxylic esters and analogs | journal = Journal of Medicinal Chemistry | volume = 16 | issue = 11 | pages = 1260–7 | date = November 1973 | pmid = 4747968 | doi = 10.1021/jm00269a600 }}{{cite journal | vauthors = Kline RH, Wright J, Fox KM, Eldefrawi ME | title = Synthesis of 3-arylecgonine analogues as inhibitors of cocaine binding and dopamine uptake | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 7 | pages = 2024–7 | date = July 1990 | pmid = 2362282 | doi = 10.1021/jm00169a036 }} the relative scarcity of methylecgonidine and the demanding reaction conditions required for the synthesis{{cite journal | vauthors = Xu L, Trudell ML | title = Stereoselective Synthesis of 2β-Carbomethoxy-3β-Phenyltropane Derivatives. Enhanced Stereoselectivity Observed for the Conjugate Addition Reaction of Phenylmagnesium Bromide Derivatives with Anhydro Dichloromethane | journal = Journal of Heterocyclic Chemistry | year = 1996 | volume = 33 | issue = 6 | pages = 2037–2039 | doi = 10.1002/jhet.5570330676}}{{cite journal | vauthors = Milius RA, Saha JK, Madras BK, Neumeyer JL | title = Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor | journal = Journal of Medicinal Chemistry | volume = 34 | issue = 5 | pages = 1728–31 | date = May 1991 | pmid = 2033595 | doi = 10.1021/jm00109a029 }} 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
The legal status of troparil is unclear, but it may be considered a controlled substance analog of cocaine in the United States on the grounds of its related chemical structure. The legal status of troparil and many other cocaine analogs in Canada, is dependent on if ecgonine, coca, or cocaine were derivatives of the compound, according to the wording on the entry of coca in Schedule 1 of the Controlled Drugs and Substances Act.{{cite web|url=http://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-24.html#h-28|title=Controlled Drugs and Substances Act (S.C. 1996, c. 19) | work = Department of Justice | publisher = Government of Canada |url-status=dead|archive-url=https://web.archive.org/web/20120107012749/http://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-24.html|archive-date= 7 January 2012 }}
See also
References
{{reflist}}
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
{{Phenyltropanes}}
Category:Dopamine reuptake inhibitors