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m Schedule II. Derivative of Ecgonine. From 21 U.S. Code 812(a)(4); “[C]oca leaves, except coca leaves and extracts of coca leaves from which cocaine, ecgonine, and derivatives of ecgonine or their salts have been removed; cocaine, its salts, optical and geometric isomers, and salts of isomers; ecgonine, its derivatives, their salts, isomers, and salts of isomers; or any compound, mixture, or preparation which contains any quantity of any of the substances referred to in this paragraph”.
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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
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| verifiedrevid = 401634603
| Watchedfields = changed
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| IUPAC_name = methyl (1R,2S,3S,5S)-8-methyl-3-phenyl -8-azabicyclo[3.2.1]octane-2-carboxylate
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| verifiedrevid = 447760207
| image = Troparil.png
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| IUPAC_name = Methyl (1''R'',2''S'',3''S'',5''S'')-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate
| image = Phenyltropane 11a - WIN 35065-2 - Troparil.svg
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 298684


<!--Clinical data-->
<!--Clinical data-->| tradename =
| tradename =
| pregnancy_AU =
| pregnancy_AU =
| pregnancy_US =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| pregnancy_category =
| legal_AU =
| legal_CA =
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| legal_UK = PSA
| legal_CA =
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| legal_US = Schedule II
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| legal_UK = Class B
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| legal_status =
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| legal_US = Schedule II
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| routes_of_administration = <!--Pharmacokinetic data-->
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| legal_status =
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| bioavailability =
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| routes_of_administration =
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| protein_bound =
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| metabolism =
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| elimination_half-life =
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| excretion = <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
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| CAS_number = 74163-84-1
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 11M96D7J17
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| ATC_prefix = none
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| ATC_suffix =
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| PubChem = 170832
| ChemSpiderID = 149355


<!--Pharmacokinetic data-->
<!--Chemical data-->| C = 16
| H = 21
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| bioavailability =
| N = 1
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| protein_bound =
| O = 2
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| metabolism =
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| smiles = CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=CC=C3)C(=O)OC
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| elimination_half-life =
| 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
| excretion =
| StdInChIKey = OMBOXYLBBHNWHL-YJNKXOJESA-N
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| melting_point = 190
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| melting_high = 191
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}}


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'''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,<ref>{{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 }}</ref> but is less potent as a serotonin reuptake inhibitor,<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> The most commonly used form of troparil is the [[tartrate]] [[salt (chemistry)|salt]], but the [[hydrochloride]] and [[Armstrong's acid|naphthalenedisulfonate]] salts are also available, as well as the free base.
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<!--Identifiers-->
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| CAS_number = 74163-84-1
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| ATC_prefix = none
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| ATC_suffix =
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| PubChem = 170832

<!--Chemical data-->
| C=16 | H=21 | N=1 | O=2
| molecular_weight = 259.343 g/mol
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| smiles = CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=CC=C3)C(=O)OC
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| melting_point = 190
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| melting_high = 191
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}}
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'''(–)-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,<ref>{{Cite pmid|17017960}}</ref> but is less potent as a serotonin reuptake inhibitor,<ref>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</ref> 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.<ref>{{Cite pmid|19463023}}</ref> The most commonly used form of β-CPT is the [[tartrate]] salt, but the [[hydrochloride]] and [[Armstrong's acid|naphthalenedisulfonate]] salts are also available, as well as the free base.


==Background==
==Background==
The first known published synthesis of WIN 35,065-2 and [[WIN 35,428]] is by Clarke and co-workers during the 1970s.<ref>{{US patent|3813404}}</ref><ref name=Clarke/> 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 [[Norepinephrine transporter|NET]] affinity that exceeds the [[Dopamine active transporter|DAT]] affinity.
The first known published synthesis of troparil and the related compound [[WIN 35428]] is by Clarke and co-workers during the 1970s.<ref>{{US patent|3813404}}</ref><ref name=Clarke/> 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 [[Norepinephrine transporter|NET]] affinity that exceeds the [[Dopamine active transporter|DAT]] affinity.{{citation needed|date=June 2012}}


==Application & Uses==
==Application ==
Phenyltropanes are likely to have less abuse and dependency compared with cocaine.<ref>{{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 }}</ref><ref>{{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 }}</ref>
Phenyltropanes are likely to have less abuse and dependency compared with cocaine.<ref>{{Cite pmid| 15957006}}</ref><ref>{{Cite pmid|17258302}}</ref>


CPT is used in scientific research into the [[dopamine]] reuptake transporter. <sup>3</sup>H-[[Isotopic labeling|radiolabelled]] forms of CPT have been used in humans and animals to map the distribution of [[dopamine]] transporters in the [[brain]].<ref> Ritz M.C. et al. [3H]WIN 35,065-2: a ligand for cocaine receptors in striatum. J. Neurochem. 1990, 55, 1556-1562. </ref><ref> 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. </ref> It is also used for animal research into stimulant drugs as an alternative to cocaine which produces similar effects,<ref> Zakusov VV, Naumova BI. Pharmacology of troparil. Farmakologiia i Toksikologiia. 1985 Jan-Feb;48(1):15-9. </ref> but avoids the stringent licensing requirements for the use of cocaine itself.
Troparil is used in scientific research into the [[dopamine]] reuptake transporter. <sup>3</sup>H-[[Isotopic labeling|radiolabelled]] forms of troparil have been used in humans and animals to map the distribution of [[dopamine]] transporters in the [[brain]].<ref>{{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 }}</ref><ref>{{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 }}</ref> It is also used for animal research into stimulant drugs as an alternative to cocaine which produces similar effects,<ref>{{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 }}</ref> but avoids the stringent licensing requirements for the use of cocaine itself.


β-CPT has similar effects to cocaine in animal studies,<ref>{{Cite pmid|1797525}}</ref><ref>{{Cite pmid|9083474}}</ref> but recreational use of this compound to date has proven extremely rare. Despite being easily made by the reaction of [[methylecgonidine]] with [[phenylmagnesium bromide]],<ref name=Clarke>{{Cite pmid|4747968}}</ref><ref>{{Cite pmid|2362282}}</ref> the relative scarcity of methylecgonidine and the demanding reaction conditions required for the synthesis<ref>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.</ref><ref>{{Cite pmid|2033595}}</ref> 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.
Troparil has similar effects to cocaine in animal studies,<ref>{{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 }}</ref><ref>{{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 }}</ref> but recreational use of this compound to date has proven extremely rare. Despite being easily made by the reaction of [[methylecgonidine]] with [[phenylmagnesium bromide]],<ref name=Clarke>{{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 }}</ref><ref>{{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 }}</ref> the relative scarcity of methylecgonidine and the demanding reaction conditions required for the synthesis<ref>{{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}}</ref><ref>{{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 }}</ref> 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 ==
== Legality ==


The legal status of troparil is unclear, but it may be considered a [[Federal Analog Act|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]].<ref>{{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 }}</ref>
The legal status of CPT is unclear. [[Sigma-Aldrich]] claims that it is a Schedule II / Class B drug in the USA and UK,<ref>[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIGMA/C156 Sigma-Aldrich pharmaceutical page for Troparil/CPT]</ref> 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 [[Federal Analog Act|controlled substance analogue]] of cocaine on the grounds of its related chemical structure in some jurisdictions such as [[Australia]] and [[New Zealand]].


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== See also ==
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 drug]]s such as [[Alphamethylfentanyl|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.
* [[List of phenyltropanes]]

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==See also==
* [[WIN 35,428]]
* [[List of cocaine analogues]]
* [[List of cocaine analogues]]
* [[WIN 25,978]]
* [[Amfonelic acid]]


== References ==
== References ==
{{reflist}}
{{reflist}}


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{{Phenyltropanes}}
{{Stimulants}}
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
{{Dopaminergics}}
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{{Phenyltropanes}}


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[[Category:Tropanes]]
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[[Category:Stimulants]]
[[Category:Sympathomimetic amines]]
[[Category:Sympathomimetic amines]]
[[Category:Phenyl compounds]]
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