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			{{Short description|Stimulant drug}}
			{{redirect-distinguish|Nocaine|Norcocaine}}
	{{Drugbox		{{Drugbox
			| Verifiedfields = changed
	| verifiedrevid = 438331863
			| Watchedfields = changed
	|IUPAC_name = methyl (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
			| verifiedrevid = 445600638
			| IUPAC_name = Methyl (3''R'',4''S'')-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
	| image = (+)-CPCA.svg		| image = (+)-CPCA.svg
	| width = 200		| width = 200
	| CAS_number=
			<!--Clinical data-->
	| ATC_prefix=none
			| tradename =
	| ATC_suffix=
			| routes_of_administration =
	| PubChem= 10333222
			<!--Identifiers-->
			| CAS_number_Ref = {{cascite|correct|??}}
			| CAS_number = 263769-22-8
			| ATC_prefix = none
			| PubChem = 10333222
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
			| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
	| DrugBank=
			| ChemSpiderID = 8508681
	| C=14 | H=18 | Cl=1 | N=1 | O=2
	| molecular_weight = 267.751 g/mol
			<!--Chemical data-->
	| smiles = COC(=O)C1CN(C)CCC1c(cc2)ccc2Cl
			| C=14 | H=18 | Cl=1 | N=1 | O=2
	| bioavailability=
			| smiles = Clc1ccc(cc1)2(C(=O)OC)CN(C)CC2
	| metabolism =
			| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
	| elimination_half-life=
			| StdInChI = 1S/C14H18ClNO2/c1-16-8-7-12(13(9-16)14(17)18-2)10-3-5-11(15)6-4-10/h3-6,12-13H,7-9H2,1-2H3/t12-,13+/m1/s1
	| excretion =
			| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
	| pregnancy_category =
			| StdInChIKey = GDFVYUDIAQQDTA-OLZOCXBDSA-N
	| legal_status =
	| routes_of_administration=
	}}		}}
	:''"Nocaine" redirects here, and is not to be confused with "]"''
	'''(+)-CPCA''' ('''nocaine''', '''3α-carbomethoxy-4β-(4-chlorophenyl)-N-methylpiperidine''') is a ] drug similar in structure to ], but lacking the two-carbon bridge of the ] skeleton <ref name=nocaine>{{Cite pmid|9599245}}</ref> This compound was first developed as a substitute agent for cocaine.
			'''(+)-CPCA''' ('''nocaine''', '''3α-carbomethoxy-4β-(4-chlorophenyl)-''N''-methylpiperidine''' aka '''CTDP 31,446'''<ref name="MobeleKinahan2006">{{cite journal| vauthors = Mobele BI, Kinahan T, Ulysse LG, Gagnier SV, Ironside MD, Knox GS, Mohammadi F |title=Process Development toward the Pilot Scale Synthesis of the Piperidine-Based Cocaine Analogue and Potent Dopamine and Norepinephrine Reuptake Inhibitor CTDP 31,446|journal=Organic Process Research & Development|volume=10|issue=5|year=2006|pages=914–920 |doi=10.1021/op060114g}}</ref>) is a ] drug similar in structure to ] (an opioid that possesses ] actions) and to ], but nocaine lacks the two-carbon bridge of RTI-31's ] skeleton.<ref name=cocaine>{{cite journal | vauthors = Kozikowski AP, Araldi GL, Boja J, Meil WM, Johnson KM, Flippen-Anderson JL, George C, Saiah E | display-authors = 6 | title = Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 11 | pages = 1962–1969 | date = May 1998 | pmid = 9599245 | doi = 10.1021/jm980028+ }}</ref> This compound was first developed as a substitute agent for cocaine.
	Since this time a large number of substituted ]] derivatives have been discovered, hybridizing the basic nocaine structure with that of other similar molecules such as ], ] and ] to create a large family of derivatives with a range of activity profiles and potential applications. This is a significant field of research with much work ongoing, and dozens of novel compounds have been developed although none have yet come to market.
			Since then, many substituted ] derivatives have been discovered, hybridizing the basic nocaine structure with that of other similar molecules such as ], ] and ] to create a large family of derivatives with a range of activity profiles and potential applications. This is a significant field of research with much ongoing work, with dozens of novel compounds having been developed although none have yet come to market.
	The Nocaine family includes a diverse assortment of piperidine based cocaine mimics. The parent compound Nocaine was developed in an attempt to develop a substitute drug for ] for the treatment of addiction, and was found to substitute for cocaine in animal models while having significantly less abuse potential itself.
			The nocaine family includes a diverse assortment of piperidine based cocaine mimetics. The parent compound nocaine was developed in an attempt to create a substitute drug for ] for the treatment of addiction, and was found to substitute for cocaine in animal models while having significantly less abuse potential.
	]
			==Background==
	==Routes of synthesis==
			Although ] reported compound with chlorine in 1998, plain ] was reported earlier than this by Plati.
	To make any of the phenyltropanes requires either a source of cocaine, or extensive and repeated separation of enantiomers due to the lack of enantioselective routes to the essential intermediate ] and the large differences in potency between different structural isomers of the final product.<ref name=Clarke>{{Cite pmid|4747968}}</ref>
			Although novel ways to produce these compounds exist, background stems from ] chemistry. E.g. ] (''Paxil'') and ] also from this arena of ] ]. These serotonin based antidepressants, in case of ] ''N''-normethyl also some ] according to texts.{{cn|date=June 2020}}
	Laboratory synthesis has been devised <ref></ref> but is hampered by the fact that in addition to the wanted isomer of anhydroecgonidine, they are also saddled with the unwanted enantiomer.
			Further nocaine derivatives were developed for treating addiction from Kozikowski's teachings:<ref name="EP2617704">{{Cite patent|country=EP|number=2617704|pubdate=2017-06-28|title=Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors|assign1=Sunovion Pharmaceuticals Inc.|inventor1-last=Shao|inventor1-first=Liming|inventor2-last=Wang|inventor2-first=Fengjiang|inventor3-last=Malcolm|inventor3-first=Scott Christopher|inventor4=Michael Charles Hewitt;Jianguo Ma;Seth Ribe;Mark A. Varney;Una Campbell;Sharon Rae Engel;Larry Wendell Hardy;Patrick Koch;Rudy Schreiber;Kerry L Spear}}</ref> Smith specifically states that the butyrophenone analog of nocaine is an active agent, as well as specifying pthalimide type alkylamino agents.{{citation needed|date=June 2021}}
	==Basic Pharmacology==
			]
	Like cocaine, (–)-cis-CPCA and (+)-CPCA bind to the ] and inhibit ] uptake, stimulate motor activity in rodents and completely substitute for cocaine in discrimination tests. Pretreatment with (–)-cis-CPCA or (+)-CPCA enhances the cocaine discriminative stimulus in rats. However there are a number of differences; the locomotor stimulant effects of the piperidine derivatives are much less than those induced by cocaine, and pretreating mice with (–)-cis-CPCA or (+)-CPCA does not increase cocaine induced convulsions, and actually reduced cocaine induced locomotor stimulation. The (–)-cis-CPCA isomer has similar reinforcing effects to cocaine as shown by fixed-ratio self-administration tests in rats, but (+)-CPCA has a flat dose-response curve, and similarly while (–)-cis-CPCA and cocaine had nearly identical break points in a "punished responding" (?) self administration test, (+)-CPCA had a lower break point than either of the other drugs.
			Further support lends a scale-up process that also relies on arecoline, which is toxic and already active pharmaceutical salt:<ref name = "MobeleKinahan2006" />
			The Ketanserin analog devised by Peter Meltzer uses an altogether different methodology of synthesis:<ref>{{cite journal | vauthors = Provencher BA, Eshleman AJ, Johnson RA, Shi X, Kryatova O, Nelson J, Tian J, Gonzalez M, Meltzer PC, Janowsky A | display-authors = 6 | title = Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 20 | pages = 9121–9131 | date = October 2018 | pmid = 30240563 | doi = 10.1021/acs.jmedchem.8b00542 | s2cid = 52312790 }}</ref> The same procedure was employed years earlier for ], and was known from before this from RTI diaryltropanes.<ref name="Jiang_1998">{{cite journal | vauthors = Jiang S, Chang AC, Abraham P, Kuhar MJ, Carroll FI | title = Synthesis and transporter binding properties of (R)-2β,3β- and (R)-2α,3α-diaryltropanes | journal = Bioorganic & Medicinal Chemistry Letters | volume = 8 | issue = 24 | pages = 3689–92 | date = December 1998 | pmid = 9934496 | doi = 10.1016/s0960-894x(98)00673-8 }}</ref> Thus, these methods are now well known in the art and do not necessarily rely on the use of arecoline as a starting material.
			The Warner-Lambert Butler synthesis for example uses a 4-phenylnicotinic acid starting material: {{US patent|4745123}} citing:<ref>{{cite journal | vauthors= Hauck AE, Giam CS | journal=Journal of the Chemical Society, Perkin Transactions 1 | title=Regioselective nucleophilic addition of organolithium compounds to 3-(4,4-dimethyloxazolin-2-yl)pyridine | pages=2070 | date= 1980 | doi=10.1039/p19800002070}}</ref>
			=== 3',4'-Dichloro Advocacy ===
			The method of improving the cited Ki by 3',4'-dichlorophenyl is now well known in the art and is heavily patented.<ref>{{cite journal | vauthors = Shao L, Li W, Xie Q, Yin H | title = Triple reuptake inhibitors: a patent review (2006 - 2012) | journal = Expert Opinion on Therapeutic Patents | volume = 24 | issue = 2 | pages = 131–154 | date = February 2014 | pmid = 24289044 | doi = 10.1517/13543776.2014.859676 | s2cid = 1825304 }}</ref>
			#piperidine-brasofensine {{US patent|6376673}}
			#piperidine-tesofensine<ref>{{cite patent|country=US|number=7560562|pubdate=2009-07-14|title=Piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors|assign1=Neuroesearch AS|inventor1-last=Wätjen|inventor1-first=Frank}}</ref> {{US patent|20060094759}}
			#Ritalin,<ref>{{cite journal | vauthors = Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM | title = Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs | journal = Journal of Medicinal Chemistry | volume = 39 | issue = 6 | pages = 1201–1209 | date = March 1996 | pmid = 8632426 | doi = 10.1021/jm950697c }}</ref><ref>{{cite journal | vauthors = Schweri MM, Deutsch HM, Massey AT, Holtzman SG | title = Biochemical and behavioral characterization of novel methylphenidate analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 301 | issue = 2 | pages = 527–535 | date = May 2002 | pmid = 11961053 | doi = 10.1124/jpet.301.2.527 }}</ref>
			#Meperidine,<ref>{{cite journal | vauthors = Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML | title = Synthesis and biological evaluation of meperidine analogues at monoamine transporters | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 5 | pages = 1336–1343 | date = March 2005 | pmid = 15743177 | doi = 10.1021/jm0401614 }}</ref><ref>{{cite journal | vauthors = Rhoden JB, Bouvet M, Izenwasser S, Wade D, Lomenzo SA, Trudell ML | title = Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters | journal = Bioorganic & Medicinal Chemistry | volume = 13 | issue = 19 | pages = 5623–5634 | date = October 2005 | pmid = 15993612 | doi = 10.1016/j.bmc.2005.05.025 }}</ref>
			#sertraline
			#indatraline
			#]
			#sibutramine:<ref>{{cite journal | vauthors = Shao L, Hewitt MC, Wang F, Malcolm SC, Ma J, Campbell JE, Campbell UC, Engel SR, Spicer NA, Hardy LW, Schreiber R, Spear KL, Varney MA | display-authors = 6 | title = Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 5 | pages = 1438–1441 | date = March 2011 | pmid = 21310609 | doi = 10.1016/j.bmcl.2011.01.016 }}</ref><ref>{{cite journal | vauthors = Shao L, Hewitt MC, Wang F, Malcolm SC, Ma J, Campbell JE, Campbell UC, Engel SR, Spicer NA, Hardy LW, Schreiber R, Spear KL, Varney MA | display-authors = 6 | title = Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 5 | pages = 1434–1437 | date = March 2011 | pmid = 21310612 | doi = 10.1016/j.bmcl.2011.01.019 }}</ref>
			#mazindol
			#]
			#tramadol<ref name="EP2617704" />
			#]
			#]
			#]
			#]
			==Pharmacology==
			Like cocaine, (−)-cis-CPCA and (+)-CPCA bind to the ] and inhibit ] uptake, stimulate motor activity in rodents and completely substitute for cocaine in discrimination tests. Pretreatment with (−)-cis-CPCA or (+)-CPCA enhances the cocaine discriminative stimulus in rats. However, there are a number of differences; the ] effects of the piperidine derivatives are much less than those induced by cocaine, and pretreating mice with (−)-cis-CPCA or (+)-CPCA does not increase cocaine induced convulsions, and actually reduced cocaine induced locomotor stimulation. The (−)-cis-CPCA isomer has similar reinforcing effects to cocaine as shown by fixed-ratio self-administration tests in rats, but (+)-CPCA has a flat dose-response curve, and similarly while (−)-cis-CPCA and cocaine had nearly identical break points in a "punished responding" (?) self-administration test, (+)-CPCA had a lower break point than either of the other drugs.
	{| class="wikitable"		{| class="wikitable"
	|colspan=4|Monoamine Reuptake Activity (nM)		|colspan=4|''Monoamine Reuptake Activity (nM)''
	|-		|-
	|Compound||NE||5-HT||DA		|'''Compound'''||'''NE'''||5-HT'''||DA'''
	|-		|-
	|Cocaine||119||177||275		|Cocaine||119||177||275
	|-		|-
	|(–)-cis-CPCA||98||390||67		|(−)-cis-CPCA||98||390||67
	|-		|-
	|(+)-CPCA||90||5900||276		|(+)-CPCA||90||5900||276
	|-		|-
	|}		|}
	The generally lower efficacy of (+)-CPCA in locomotor and methamphetamine discrimination tests could result from the differential selectivity of the two isomers for the DAT relative to the SERT. That is, if serotonin receptor activation is requisite for maximal efficacy, the difference SERT affinity between (–)-cis-CPCA and (+)-CPCA might play a contributory role in accounting for the differences in the observed pharmacology. Catecholamine selective drugs, like TMP (methylphenidate), are reported to possess decent abuse potential though, so it is not easy to gauge why (+)-CPCA does not entice a strong self-administration propensity.
			The generally lower efficacy of (+)-CPCA in locomotor and methamphetamine discrimination tests could result from the differential selectivity of the two isomers for the DAT relative to the SERT. That is, if serotonin receptor activation is requisite for maximal efficacy, the difference SERT affinity between (−)-cis-CPCA and (+)-CPCA might play a contributory role in accounting for the differences in the observed pharmacology. Catecholamine selective drugs, like TMP (methylphenidate), are reported to possess decent abuse potential though, so it is not easy to gauge why (+)-CPCA does not entice a strong self-administration propensity.
	A possible explanation might be nocaine preferentially binds to the ↓ DAT, in which case it would be expected to behave somewhat differently to cocaine.<ref>{{Cite pmid|15743177}}</ref> Some sort of cholinergic effect might also be aversive. For example, muscarinic activity of benztropine analogs is known to limit their reinforcing potential.<ref>{{Cite pmid|17034144}}</ref> Ion-channel activity is another factor that can be used to explain certain differences in pharmacology.
			A possible explanation might be nocaine preferentially binds to the ↓ DAT, in which case it would be expected to behave somewhat differently from cocaine.<ref name="Lomenzo"/> Some sort of cholinergic effect might also be aversive. For example, muscarinic activity of benztropine analogs is known to limit their reinforcing potential.<ref>{{cite journal | vauthors = Zou MF, Cao J, Kopajtic T, Desai RI, Katz JL, Newman AH | title = Structure-activity relationship studies on a novel series of (S)-2beta-substituted 3alpha-tropane analogues for in vivo investigation | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 21 | pages = 6391–6399 | date = October 2006 | pmid = 17034144 | doi = 10.1021/jm060762q }}</ref> Ion-channel activity is another factor that can be used to explain certain differences in pharmacology.
	It is possible that ] activity might also account for some of the differences between cocaine and these piperidine mimics (R. Matsumoto, et al. 2001,<ref>{{Cite pmid|11684152}}</ref><ref>{{Cite pmid|11426838}}</ref><ref>{{Cite pmid|12128006}}</ref><ref>{{Cite pmid|12782179}}</ref> (Ping and Teruo, 2003 rev).<ref>{{Cite pmid|12871086}}</ref> Sigma receptors are not specific to cocaine, other psychostimulants like methamphetamine (E. Nguyen, et al. 2005),<ref>{{Cite pmid|15939443}}</ref> and phencyclidine are also linked to this neural target. An increased understanding of this receptor recently led to a novel AD being reported that is based around its pharmacology.<ref>{{Cite pmid|17376658}}</ref>
			It is possible that ] activity might also account for some of the differences between cocaine and these piperidine mimics (R. Matsumoto, et al. 2001,<ref>{{cite journal | vauthors = Matsumoto RR, Hewett KL, Pouw B, Bowen WD, Husbands SM, Cao JJ, Newman AH | title = Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters | journal = Neuropharmacology | volume = 41 | issue = 7 | pages = 878–886 | date = December 2001 | pmid = 11684152 | doi = 10.1016/S0028-3908(01)00116-2 | s2cid = 44328858 }}</ref><ref>{{cite journal | vauthors = Matsumoto RR, McCracken KA, Friedman MJ, Pouw B, De Costa BR, Bowen WD | title = Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice | journal = European Journal of Pharmacology | volume = 419 | issue = 2–3 | pages = 163–174 | date = May 2001 | pmid = 11426838 | doi = 10.1016/S0014-2999(01)00968-2 }}</ref><ref>{{cite journal | vauthors = Matsumoto RR, McCracken KA, Pouw B, Zhang Y, Bowen WD | title = Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides | journal = Neuropharmacology | volume = 42 | issue = 8 | pages = 1043–1055 | date = June 2002 | pmid = 12128006 | doi = 10.1016/S0028-3908(02)00056-4 | s2cid = 34846910 }}</ref><ref>{{cite journal | vauthors = Matsumoto RR, Liu Y, Lerner M, Howard EW, Brackett DJ | title = Sigma receptors: potential medications development target for anti-cocaine agents | journal = European Journal of Pharmacology | volume = 469 | issue = 1–3 | pages = 1–12 | date = May 2003 | pmid = 12782179 | doi = 10.1016/S0014-2999(03)01723-0 }}</ref> (Ping and Teruo, 2003 rev).<ref>{{cite journal | vauthors = Su TP, Hayashi T | title = Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction | journal = Current Medicinal Chemistry | volume = 10 | issue = 20 | pages = 2073–2080 | date = October 2003 | pmid = 12871086 | doi = 10.2174/0929867033456783 | url = https://zenodo.org/record/1235850 }}</ref> Sigma receptors are not specific to cocaine, other psychostimulants like methylphenidate, methamphetamine (E. Nguyen, et al. 2005),<ref>{{cite journal | vauthors = Nguyen EC, McCracken KA, Liu Y, Pouw B, Matsumoto RR | title = Involvement of sigma (sigma) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies | journal = Neuropharmacology | volume = 49 | issue = 5 | pages = 638–645 | date = October 2005 | pmid = 15939443 | doi = 10.1016/j.neuropharm.2005.04.016 | s2cid = 41068558 }}</ref> and phencyclidine are also linked to this neural target. An increased understanding of this receptor recently led to a novel AD being reported that is based around its pharmacology.<ref>{{cite journal | vauthors = Wang J, Mack AL, Coop A, Matsumoto RR | title = Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice | journal = European Neuropsychopharmacology | volume = 17 | issue = 11 | pages = 708–716 | date = November 2007 | pmid = 17376658 | pmc = 4041597 | doi = 10.1016/j.euroneuro.2007.02.007 }}</ref>
	In summary, (+)-CPCA has lower potency and efficacy than cocaine in increasing locomotor activity in rodents. (+)-CPCA only manages to produce partial methamphetamine-like discriminative stimulus effects, although it is fully cocaine-like in cocaine-trained animals. (+)-CPCA has lower reinforcing potential than cocaine as assessed by fixed and progressive ratio IV self-administration tests in rats, with its reinforcing effects confirmed by rhesus monkeys. Furthermore, (+)-CPCA dose dependently antagonizes cocaine-induced locomotion and potentiates the discriminative stimulus effects of a low dose of cocaine. (+)-CPCA, unlike cocaine, does not enhance cocaine-induced convulsions. These results suggest that (+)-CPCA completely mimics certain behavioral actions of cocaine, whereas acting like a weak partial agonist in others, including its ability to attenuate cocaine-induced increase in locomotion and to serve as a positive reinforcing agent in rodents. Thus, (+)-CPCA may have potential utility in the treatment of cocaine addiction, and also offer valuable pharmacological information, furthering our understanding of cocaines mechanism of action, because it exhibits fundamental differences from other related DARI molecules.
			In summary, (+)-CPCA has lower potency and efficacy than cocaine in ] in rodents. (+)-CPCA only manages to produce partial methamphetamine-like discriminative stimulus effects, although it is fully cocaine-like in cocaine-trained animals. (+)-CPCA has lower reinforcing potential than cocaine as assessed by fixed and progressive ratio IV self-administration tests in rats, with its reinforcing effects confirmed by rhesus monkeys. Furthermore, (+)-CPCA dose dependently antagonizes cocaine-induced locomotion and potentiates the discriminative stimulus effects of a low dose of cocaine. (+)-CPCA, unlike cocaine, does not enhance cocaine-induced convulsions. These results suggest that (+)-CPCA completely mimics certain behavioral actions of cocaine, whereas acting like a weak partial agonist in others, including its ability to attenuate cocaine-induced increase in locomotion and to serve as a positive reinforcing agent in rodents. Thus, (+)-CPCA may have potential utility in the treatment of cocaine addiction, and also offer valuable pharmacological information, furthering our understanding of cocaine's mechanism of action, because it exhibits fundamental differences from other related DARI molecules.
	==Nocaine: Ester and Amine Modifications==
	A series of novel N- and 3α-modified Nocaine analogs were synthesized and tested for their ] activity and behavioral properties in mice.<ref>{{Cite pmid|12109901}}</ref>
			==Chemistry==
	The rational design of ligands with a predetermined potency at and selectivity for monoamine transporters is hindered by the lack of knowledge about the 3D structure of these targets. In cases where the 3D structure of the binding site in a target protein is not well defined, as is the case for the ] proteins, one can perform ligand-based design to develop a ]. That is, by studying the conformational properties of a series of pharmacologically similar compounds, one can form hypotheses regarding the pharmacophore.<ref>{{Cite pmid|17228864}}</ref> Most of the potent tropane-based inhibitors, inc. coca, are believed to have at least 3 major interactions with the transporter binding site: one ionic or H-bonding interaction at the basic nitrogen, one dipole-dipole or H-bonding interaction of the ester group, and an interaction of the aryl group with a lipophilic binding pocket. This model was successfully used for the design of a novel piperidine-based DAT inhibitor, that is economically affordable to manufacture.<ref>{{Cite pmid|10669562}}</ref>
			===Routes of synthesis===
	Although the in vivo metabolism of (+)-CPCA is also likely to involve N-demethylation, metabolism to the corresponding free acid, to give a compound inactive at all monoamine transporters, will probably be the predominant pathway ''in vivo''. It was reasoned that metabolism via esterase action can be avoided by replacing the ester group with a bioisosteric group that is more stable to metabolic degradation. In previous studies, it was found that oxadiazole, although cocaine-like in activity, exhibits a significantly longer duration of action due to slower rate of metabolism. In general, relative to the corresponding N-methyl compounds, the norpiperidines exhibited an increased activity at the SERT/NET and only modest changes at the DAT.
			The arecoline route goes the same as for RTI-31 starting from ].<ref>{{cite journal | vauthors = Xu L, Trudell ML | journal=Journal of Heterocyclic Chemistry | title=Stereoselective synthesis of 2β-carbomethoxy-3β-phenyltropane derivatives. Enhanced stereoselectivity observed for the conjugate addition reaction of phenylmagnesium bromide derivatives with anhydro dichloromethane | volume=33 | issue=6 | pages=2037–2039 | date= November 1996 | doi=10.1002/jhet.5570330676}}</ref> Trudell lays down the groundwork for the correct procedure that was then heavily patented by SKF.
			Patented methods reported
			#Ward & Crowe SKF improved method: {{US patent|6172233}}<ref>{{Cite patent|country=WO|status=application|number=0232870|pubdate=2002-04-25|title=Process of the preparation of 3-substituted-4-aryl piperidine compounds|assign1=]|inventor1-last=Ward|inventor1-first=Neal}}</ref><ref>{{Cite patent|country=WO|number=0129032|pubdate=2001-04-26|title=Process for the preparation of paroxetine|assign1=]|status=application|inventor1-last=Crowe|inventor1-first=David|inventor2-last=Ward|inventor2-first=Neal|inventor3-last=Wells|inventor3-first=Andrew Stephen}}</ref><ref>{{Cite patent|country=WO|number=0117966|pubdate=2001-03-15|title=Process for the preparation of 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine|assign1=]|inventor1-last=Crowe|inventor1-first=David|inventor2-last=Jones|inventor2-first=David Alan|inventor3-last=Ward|inventor3-first=Neal}}</ref>
			Three theoretical improvements over the earlier historical attempts of the work of Plati & Clarke:
			#The solvent is apolar, whereas for forming the Grignard reagent the solvent needs to be ether, which is removed prior to the conjugate addition.
			#The temperature for forming the Grignard reagent needs to be reflux whereas the temperature needs to be refrigerated for the conjugate addition.
			#A catalytic amount of CuCl can encourage soft over hard addition.<ref>{{Cite web|url=https://www.organic-chemistry.org/Highlights/2005/04February.shtm|title = Copper-Catalyzed Conjugate Addition to α,β-Unsaturated Carbonyl Compounds}}</ref>
			===Ester and amine modifications===
			A series of novel N- and 3α-modified nocaine analogs were synthesized and tested for their ] activity and behavioral properties in mice.<ref>{{cite journal | vauthors = Petukhov PA, Zhang J, Kozikowski AP, Wang CZ, Ye YP, Johnson KM, Tella SR | title = SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 15 | pages = 3161–3170 | date = July 2002 | pmid = 12109901 | doi = 10.1021/jm0200153 }}</ref>
			The rational design of ligands with a predetermined potency at and selectivity for monoamine transporters is hindered by the lack of knowledge about the 3D structure of these targets. In cases where the 3D structure of the binding site in a target protein is not well defined, as is the case for the ] proteins, one can perform ligand-based design to develop a ]. That is, by studying the conformational properties of a series of pharmacologically similar compounds, one can form hypotheses regarding the pharmacophore.<ref>{{cite journal | vauthors = Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A | display-authors = 6 | title = Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 2 | pages = 219–232 | date = January 2007 | pmid = 17228864 | doi = 10.1021/jm0608614 }}</ref> Most of the potent tropane-based inhibitors, inc. coca, are believed to have at least 3 major interactions with the transporter binding site: one ionic or H-bonding interaction at the basic nitrogen, one dipole-dipole or H-bonding interaction of the ester group, and an interaction of the aryl group with a lipophilic binding pocket. This model was successfully used for the design of a novel piperidine-based DAT inhibitor, that is economically affordable to manufacture.<ref>{{cite journal | vauthors = Wang S, Sakamuri S, Enyedy IJ, Kozikowski AP, Deschaux O, Bandyopadhyay BC, Tella SR, Zaman WA, Johnson KM | display-authors = 6 | title = Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 3 | pages = 351–360 | date = February 2000 | pmid = 10669562 | doi = 10.1021/jm990516x }}</ref>
			Although the in vivo metabolism of (+)-CPCA is also likely to involve N-demethylation, metabolism to the corresponding free acid, to give a compound inactive at all monoamine transporters, will probably be the predominant pathway ''in vivo''. It was reasoned that metabolism via esterase action can be avoided by replacing the ester group with a bioisosteric group that is more stable to metabolic degradation. In previous studies, it was found that oxadiazole, although cocaine-like in activity, exhibits a significantly longer duration of action due to slower rate of metabolism. In general, relative to the corresponding N-methyl compounds, the norpiperidines exhibited an increased activity at the SERT/NET and only modest changes at the DAT.
	{| class="wikitable"		{| class="wikitable"
	|colspan=4|Ki (nM)		|colspan=4|''Ki (nM)''
	|-		|-
	|R||NE||DA||5HT		|'''R'''||'''NE'''||'''DA'''||'''5HT'''
	|-		|-
	|CO<sub>2</sub>Me||252 → 7.9||233 → 279||8490 → 434		|CO{{sub|2}}Me||252 → 7.9||233 → 279||8490 → 434
	|-		|-
	|CH2OH||198 → 69||497 → 836||1550 → 239		|CH2OH||198 → 69||497 → 836||1550 → 239
Line 77:		Line 124:
	|}		|}
	An interesting difference between cocaine, ester '''1a''', alcohol '''2a''', and norester '''1b''' is that the latter two compounds are substantially longer acting than cocaine in locomotor activity tests in mice. Although prolonged action is anticipated from compounds like alcohol '''2a''' and oxadiazole '''3a''' which lack the 3α ester group and so are more difficult to metabolise, this is not expected for the norester '''1b''', because the 3α ester group should be just as easily hydrolysed as the ester group of cocaine and '''1a'''. Another result of N-demethylation is an initial depressant action of '''1b''' followed by delayed locomotor stimulation, which might be due to interaction with GABA receptors or ].<ref>{{Cite pmid|11528416}}</ref>		An interesting difference between cocaine, ester '''1a''', alcohol '''2a''', and norester '''1b''' is that the latter two compounds are substantially longer acting than cocaine in locomotor activity tests in mice. Although prolonged action is anticipated from compounds like alcohol '''2a''' and oxadiazole '''3a''' which lack the 3α ester group and so are more difficult to metabolise, this is not expected for the norester '''1b''', because the 3α ester group should be just as easily hydrolysed as the ester group of cocaine and '''1a'''. Another result of N-demethylation is an initial depressant action of '''1b''' followed by delayed locomotor stimulation, which might be due to interaction with GABA receptors or ].<ref>{{cite journal | vauthors = Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F | display-authors = 6 | title = Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice | journal = Nature Neuroscience | volume = 4 | issue = 9 | pages = 873–874 | date = September 2001 | pmid = 11528416 | doi = 10.1038/nn0901-873 | s2cid = 1314227 }}</ref>
	==3α-Substituted Nocaine Ligand Design==		===3β-Substituted nocaine ligand design===
	In an earlier study, it was found that 3α-amido and bulky 3α-oxadiazoyl nocaine ligands, which possess greater stability relative to the ester functional group, and are therefore more attractive as potential therapies, are inactive. This result led to the hypothesis that the binding site of the DAT and NET in close proximity to the 3α-position of the piperidine ring is compact and cannot accommodate bulky, sterically occluded substituents, like the 3-substituted 1,2,4-oxadiazolyl groups. Supplied with this information, it was reasoned that introduction of a methylene spacer would confer improved monoamine transporter binding affinity upon the resultant molecules.<ref>{{Cite pmid|15163183}}</ref>		In an earlier study, it was found that 3α-amido and bulky 3α-oxadiazoyl nocaine ligands, which possess greater stability relative to the ester functional group, and are therefore more attractive as potential therapies, are inactive. This result led to the hypothesis that the binding site of the DAT and NET in close proximity to the 3α-position of the piperidine ring is compact and cannot accommodate bulky, sterically occluded substituents, like the 3-substituted 1,2,4-oxadiazolyl groups. It was reasoned that introduction of a methylene spacer would confer improved monoamine transporter binding affinity upon the resultant molecules.<ref>{{cite journal | vauthors = Petukhov PA, Zhang J, Wang CZ, Ye YP, Johnson KM, Kozikowski AP | title = Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 12 | pages = 3009–3018 | date = June 2004 | pmid = 15163183 | doi = 10.1021/jm0303296 }}</ref>
	]		]
	{| class="wikitable"		{| class="wikitable"
	|R||DA||5-HT||NE		|'''R'''||DA'''||5-HT'''||'''NE'''
	|-		|-
	|CO<sub>2</sub>Me||233||8490||252		|CO{{sub|2}}Me||233||8490||252
	|-		|-
	|CONMe<sub>2</sub>||2140||18900||569		|CONMe{{sub|2}}||2140||18900||569
	|-		|-
	|CH<sub>2</sub>OAc||599||901||235		|CH{{sub|2}}OAc||599||901||235
	|-		|-
	|CH<sub>2</sub>OCH<sub>2</sub>CH=CH<sub>2</sub>||60||231||20		|CH{{sub|2}}OCH{{sub|2}}CH=CH{{sub|2}}||60||231||20
	|-		|-
	|CH<sub>2</sub>CO<sub>2</sub>Et||79||191||101		|CH{{sub|2}}CO{{sub|2}}Et||79||191||101
	|-		|-
	|CH<sub>2</sub>CONMe<sub>2</sub>||16||1994||46		|CH{{sub|2}}CONMe{{sub|2}}||16||1994||46
	|-		|-
	|Heterocycle||44||32||52		|Heterocycle||44||32||52
	|-		|-
	|CH<sub>2</sub>CH<sub>2</sub>CO<sub>2</sub>Me||68||255||31		|CH{{sub|2}}CH{{sub|2}}CO{{sub|2}}Me||68||255||31
	|-		|-
	|''trans''-CH=CHCO<sub>2</sub>Me||53||501||272		|''trans''-CH=CHCO{{sub|2}}Me||53||501||272
	|-		|-
	|Pr<sup>n</sup>||20||228||6.5		|Pr{{sup|n}}||20||228||6.5
	|-		|-
	|(CH<sub>2</sub>)<sub>3</sub>OH||16||2810||564		|(CH{{sub|2}}){{sub|3}}OH||16||2810||564
	|}		|}
	One of the possible reasons that the C2–C3 compounds are more active than the C1 compounds is that the polar group present in the more flexible 3α-appendage of the C2–C3 ligands is able to avoid unfavorable interactions with the binding site in close proximity to the piperidine ring. For the same reason the appendage in the C2–C3 series may more closely, but not precisely, mimic the binding mode of the more active '''''SS''''' based ligands, and possibly even transfer over to tropane based compounds (cf. Brasofensine).		One of the possible reasons that the C2–C3 compounds are more active than the C1 compounds is that the polar group present in the more flexible 3α-appendage of the C2–C3 ligands is able to avoid unfavorable interactions with the binding site in close proximity to the piperidine ring. For the same reason the appendage in the C2–C3 series may more closely, but not precisely, mimic the binding mode of the more active ''SS'' based ligands, and possibly even transfer over to tropane based compounds.
	To better understand the difference between the C1 and the C2–C3 series, the compounds were energy minimized and flexibly superimposed on ]. The resulting overlay shows that only the C2–C3 ligands are able to adopt a conformation in which the polar group of the 3α-substituent occupies the position proximal to that of the 2β-polar group in WIN35428.		To better understand the difference between the C1 and the C2–C3 series, the compounds were energy minimized and flexibly superimposed on ]. The resulting overlay shows that only the C2–C3 ligands are able to adopt a conformation in which the polar group of the 3α-substituent occupies the position proximal to that of the 2β-polar group in WIN35428.
			===Nocaine: sulfur appendage===
	==DAT Arylpiperidine CoMFA Study==
			]
	(Hongbin Yuan, et al. 2004)<ref name="Cite pmid|15566285">{{Cite pmid|15566285}}</ref>
			]
			== Pharmacophore ==
	A generally recognized pharmacophore model for cocaine and ]s comprises two electrostatic interactions of the basic nitrogen and the ester group of the C-2 substituent, and one hydrophobic interaction of the C-3 aryl group. This model has been disputed because of the finding that in certain compounds neither the basic N nor the ester group was necessary for high binding affinity and inhibition of MAR. Instead, a hydrophobic pocket was proposed to exist in the vicinity of the C-2 carbon. Carroll et al., however, provided further evidence for an electrostatic interaction at the C-2β-position in a later study.
			A generally recognized ] model for cocaine and ]s comprises two electrostatic interactions of the basic nitrogen and the ester group of the C-2 substituent, and one hydrophobic interaction of the C-3 aryl group.<ref name="Cite pmid|15566285">{{cite journal | vauthors = Yuan H, Kozikowski AP, Petukhov PA | title = CoMFA study of piperidine analogues of cocaine at the dopamine transporter: exploring the binding mode of the 3 alpha-substituent of the piperidine ring using pharmacophore-based flexible alignment | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 25 | pages = 6137–6143 | date = December 2004 | pmid = 15566285 | doi = 10.1021/jm049544s }}</ref> This model has been disputed because of the finding that in certain compounds neither the basic N nor the ester group was necessary for high binding affinity and inhibition of MAR. Instead, a hydrophobic pocket was proposed to exist in the vicinity of the C-2 carbon. Carroll et al., however, provided further evidence for an electrostatic interaction at the C-2β-position in a later study.
	Other models proposed for the DAT binding site include a linear fashion binding pocket for the 3β-substituted phenyltropane analogs,<ref name=Lieske>{{Cite pmid|9526561}}</ref> and a prohibited conical region about 5.5–10Å distant from the 3α-substituted piperidine ring.<ref>{{Cite pmid|11514143}}</ref> Noticeably, high potency at the DAT of dimeric piperidine-based esters and amides suggested that the flexible linker combining the two piperidine units was able to adjust its orientation and to avoid unfavorable interactions with the binding site.<ref>{{Cite pmid|11334571}}</ref> All these lines of evidence suggest that the DAT binding site is much more complicated than the proposed pharmacophore models.
			Other models proposed for the DAT binding site include a linear fashion binding pocket for the 3β-substituted phenyltropane analogs,<ref name=Lieske>{{cite journal | vauthors = Lieske SF, Yang B, Eldefrawi ME, MacKerell AD, Wright J | title = (-)-3 beta-Substituted ecgonine methyl esters as inhibitors for cocaine binding and dopamine uptake | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 6 | pages = 864–876 | date = March 1998 | pmid = 9526561 | doi = 10.1021/jm970025h }}</ref> and a prohibited conical region about 5.5–10&nbsp;Å distant from the 3α-substituted piperidine ring.<ref>{{cite journal | vauthors = Petukhov PA, Zhang M, Johnson KJ, Tella SR, Kozikowski AP | title = Sar studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles | journal = Bioorganic & Medicinal Chemistry Letters | volume = 11 | issue = 16 | pages = 2079–2083 | date = August 2001 | pmid = 11514143 | doi = 10.1016/S0960-894X(01)00379-1 }}</ref> Noticeably, high potency at the DAT of dimeric piperidine-based esters and amides suggested that the flexible linker combining the two piperidine units was able to adjust its orientation and to avoid unfavorable interactions with the binding site.<ref>{{cite journal | vauthors = Tamiz AP, Bandyopadhyay BC, Zhang J, Flippen-Anderson JL, Zhang M, Wang CZ, Johnson KM, Tella S, Kozikowski AP | display-authors = 6 | title = Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 10 | pages = 1615–1622 | date = May 2001 | pmid = 11334571 | doi = 10.1021/jm000552s }}</ref> All these lines of evidence suggest that the DAT binding site is much more complicated than the proposed pharmacophore models.
	In an attempt to uncover the details of the DAT binding site, a number of 3D-QSAR studies were performed. Several QSAR/CoMFA studies focused on phenyltropanes concluded that an increased negative electrostatic potential in the regions around the 3β-substituent of the tropane ring and the para-position of the phenyl ring favored high potency in inhibiting the MATs. Wright et al. studied the role of the 3β-substituent of tropanes in binding to the DAT and blocking DA reuptake. Their CoMFA model indicated that the 3β-substituent binding site is '''barrel-shaped''' and hydrophobic interactions make a dominant contribution to the binding,<ref name=Lieske/> which is consistent with the studies of 3α-substituted tropane analogs reported by Newman et al. Newman and co-authors also studied N-substituted tropanes and concluded that the steric interaction of the N-substituent with the DAT is a principle factor for the binding affinity.
			In an attempt to uncover the details of the DAT binding site, a number of 3D-QSAR studies were performed. Several QSAR/CoMFA studies focused on phenyltropanes concluded that an increased negative electrostatic potential in the regions around the 3β-substituent of the tropane ring and the para-position of the phenyl ring favored high potency in inhibiting the MATs. Wright et al. studied the role of the 3β-substituent of tropanes in binding to the DAT and blocking DA re-uptake. Their CoMFA model indicated that the 3β-substituent binding site is '''barrel-shaped''' and hydrophobic interactions make a dominant contribution to the binding,<ref name=Lieske/> which is consistent with the studies of 3α-substituted tropane analogs reported by Newman et al. Newman and co-authors also studied N-substituted tropanes and concluded that the steric interaction of the N-substituent with the DAT is a principal factor for the binding affinity.
	]		]
			*<ref>{{cite journal | vauthors = Amat M, Bosch J, Hidalgo J, Cantó M, Pérez M, Llor N, Molins E, Miravitlles C, Orozco M, Luque J | display-authors = 6 | title = Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine | journal = The Journal of Organic Chemistry | volume = 65 | issue = 10 | pages = 3074–3084 | date = May 2000 | pmid = 10814199 | doi = 10.1021/jo991816p }}</ref><ref>{{cite journal | vauthors = Johnson TA, Jang DO, Slafer BW, Curtis MD, Beak P | title = Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines, pyrrolidines, and pyrimidinones | journal = Journal of the American Chemical Society | volume = 124 | issue = 39 | pages = 11689–11698 | date = October 2002 | pmid = 12296735 | doi = 10.1021/ja0271375 }}</ref>
	==Nocaine: Sulfur Appendage==
	]
	]
	==Patents==
	*Kowski: {{US Patent|6,806,281}} {{Cite patent|WO|0020390}}
	*Ward Neil: {{Cite patent|WO|0232870}} {{Cite patent|WO|0129032}} {{Cite patent|WO|0117966}} {{US patent|6172233}}
	See also:<ref>{{cite pmid|10814199}}</ref><ref>{{Cite doi|10.1021/ja0271375}}</ref>
	===NS===
	{{US patent|6,376,673}} {{Patent|WO|2004039778}}
	==See also==		== See also ==
	* ]		* ]
	* ]<ref>{{Cite pmid|10737754}}</ref>		* ]
			* ]<ref>{{cite journal | vauthors = Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski AP | display-authors = 6 | title = Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 6 | pages = 1215–1222 | date = March 2000 | pmid = 10737754 | doi = 10.1021/jm9905561 }}</ref>
	* ] and other modafinil hybrids<ref>{{Cite pmid|15537337}}</ref><ref>{{Cite pmid|16335921}}</ref>
			* ] and other modafinil hybrids<ref>{{cite journal | vauthors = Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP | title = Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 24 | pages = 5821–5824 | date = November 2004 | pmid = 15537337 | pmc = 1395211 | doi = 10.1021/jm040117o }}</ref><ref>{{cite journal | vauthors = He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP | title = Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 25 | pages = 7970–7979 | date = December 2005 | pmid = 16335921 | doi = 10.1021/jm050694s }}</ref>
	* ] and other meperidine analogues.<ref name=Lomenzo>{{cite pmid|15743177}}</ref>
			* ] and other ] (meperidine) analogues.<ref name=Lomenzo>{{cite journal | vauthors = Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML | title = Synthesis and biological evaluation of meperidine analogues at monoamine transporters | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 5 | pages = 1336–1343 | date = March 2005 | pmid = 15743177 | doi = 10.1021/jm0401614 }}</ref>
	* NET selective.<ref>{{Cite pmid|16621532}}</ref><ref>{{Cite pmid|16871320}}</ref>
			* NET selective.<ref>{{cite journal | vauthors = Musachio JL, Hong J, Ichise M, Seneca N, Brown AK, Liow JS, Halldin C, Innis RB, Pike VW, He R, Zhou J, Kozikowski AP | display-authors = 6 | title = Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 12 | pages = 3101–3104 | date = June 2006 | pmid = 16621532 | doi = 10.1016/j.bmcl.2006.03.066 }}</ref><ref>{{cite journal | vauthors = Zhou J | title = Norepinephrine transporter inhibitors and their therapeutic potential | journal = Drugs of the Future | volume = 29 | issue = 12 | pages = 1235–1244 | date = December 2004 | pmid = 16871320 | pmc = 1518795 | doi = 10.1358/dof.2004.029.12.855246 }}</ref>
	* Computer.<ref name="Cite pmid|15566285"/><ref>{{Cite pmid|17027270}}</ref>
			* Computer.<ref name="Cite pmid|15566285"/><ref>{{cite journal | vauthors = Yuan H, Petukhov PA | title = Improved 3D-QSAR CoMFA of the dopamine transporter blockers with multiple conformations using the genetic algorithm | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 24 | pages = 6267–6272 | date = December 2006 | pmid = 17027270 | doi = 10.1016/j.bmcl.2006.09.037 }}</ref>
	==References==		== References ==
	{{reflist|2}}		{{Reflist|30em}}
	{{Stimulants}}		{{Stimulants}}
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	{{DEFAULTSORT:Cpca}}		{{DEFAULTSORT:Cpca}}
	]		]
	]		]
	]		]
	]		]
			]