View source for (+)-CPCA


{{Drugbox
|IUPAC_name = methyl (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
| image = (+)-CPCA.svg
| width = 200
| CAS_number= 
| ATC_prefix=none
| ATC_suffix=
| PubChem= 10333222
| DrugBank=
| C=14 | H=18 | Cl=1 | N=1 | O=2
| molecular_weight = 267.751 g/mol
| smiles = COC(=O)C1CN(C)CCC1c(cc2)ccc2Cl
| bioavailability=
| metabolism =
| elimination_half-life=
| excretion =
| pregnancy_category =
| legal_status =
| routes_of_administration= 
}}
:''"Nocaine" redirects here, and is not to be confused with "[[Norcocaine]]"''
'''(+)-CPCA''' ('''nocaine''', '''3α-carbomethoxy-4β-(4-chlorophenyl)-N-methylpiperidine''') is a [[stimulant]] drug similar in structure to [[RTI-31]], but lacking the two-carbon bridge of the [[tropane]] skeleton [http://www.erowid.org/archive/rhodium/pdf/cocaine.analog.arecoline.pdf .]<ref name=nocaine>{{Cite pmid|9599245}}</ref> This compound was first developed as a substitute agent for cocaine.

Since this time a large number of substituted [[phenyl]][[piperidine]] derivatives have been discovered, hybridizing the basic nocaine structure with that of other similar molecules such as [[methylphenidate]], [[meperidine]] and [[modafinil]] 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.

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 [[cocaine]] for the treatment of addiction, and was found to substitute for cocaine in animal models while having significantly less abuse potential itself.

[[File:Tropiperidine.png|400px]]

==Routes of synthesis==
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 [[methylecgonidine]] and the large differences in potency between different structural isomers of the final product.<ref name=Clarke>{{Cite pmid|4747968}}</ref> 

Laboratory synthesis has been devised <ref>[http://www.google.com/patents?vid=5736556 US Patent 5736556]</ref> but is hampered by the fact that in addition to the wanted isomer of anhydroecgonidine, they are also saddled with the unwanted enantiomer.

==Basic Pharmacology==
Like cocaine, (–)-cis-CPCA and (+)-CPCA bind to the [[dopamine transporter]] and inhibit [[dopamine]] 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.
{| class="wikitable"
|colspan=4|Monoamine Reuptake Activity (nM)
|-
|Compound||[<sup>3</sup>H]NE||[<sup>3</sup>H]5-HT||[<sup>3</sup>H]DA 
|-
|Cocaine||119||177||275
|-
|(–)-cis-CPCA||98||390||67
|-
|(+)-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.

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.

It is possible that [[sigma receptor]] 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>

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.

==Nocaine: Ester and Amine Modifications==
A series of novel N- and 3α-modified Nocaine analogs were synthesized and tested for their [[SNDRI]] activity and behavioral properties in mice.<ref>{{Cite pmid|12109901}}</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 [[monoamine transporter]] proteins, one can perform ligand-based design to develop a [[pharmacophore]]. 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>

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"
|colspan=4|Ki (nM) 
|-
|R||NE||DA||5HT
|-
|CO<sub>2</sub>Me||252 → 7.9||233 → 279||8490 → 434
|-
|CH2OH||198 → 69||497 → 836||1550 → 239
|-
|Oxadiazole||256 → 34||187 → 189||5960 → 373
|-
|}

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 [[Metabotropic glutamate receptor 5|mGlu5]].<ref>{{Cite pmid|11528416}}</ref>

==3α-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> 

[[Image:Crack Baby.gif|left]]
{| class="wikitable"
|R||[<sup>3</sup>H]DA||[<sup>3</sup>H]5-HT||[<sup>3</sup>H]NE
|-
|CO<sub>2</sub>Me||233||8490||252
|-
|CONMe<sub>2</sub>||2140||18900||569
|-
|CH<sub>2</sub>OAc||599||901||235
|-
|CH<sub>2</sub>OCH<sub>2</sub>CH=CH<sub>2</sub>||60||231||20
|-
|CH<sub>2</sub>CO<sub>2</sub>Et||79||191||101
|-
|CH<sub>2</sub>CONMe<sub>2</sub>||16||1994||46
|-
|Heterocycle||44||32||52
|-
|CH<sub>2</sub>CH<sub>2</sub>CO<sub>2</sub>Me||68||255||31
|-
|''trans''-CH=CHCO<sub>2</sub>Me||53||501||272
|-
|Pr<sup>n</sup>||20||228||6.5
|-
|(CH<sub>2</sub>)<sub>3</sub>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).

To better understand the difference between the C1 and the C2–C3 series, the compounds were energy minimized and flexibly superimposed on [[WIN-35,428]]. 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.

==DAT Arylpiperidine CoMFA Study==
(Hongbin Yuan, et al. 2004)<ref name="Cite pmid|15566285">{{Cite pmid|15566285}}</ref> 

A generally recognized pharmacophore model for cocaine and [[phenyltropane]]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.

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.

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-poition 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.

[[Image:Yuan.gif|center]]

==Nocaine: Sulfur Appendage==
[[JZ-IV-10|Compound 16e]]
[[Image:16e chemical structure.png|180px|center]]

==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==
* [[List of cocaine analogues]]
* [[N,O-Dimethyl-4-(2-naphthyl)piperidine-3-carboxylate]]<ref>{{Cite pmid|10737754}}</ref>
* [[JZ-IV-10]] and other modafinil hybrids<ref>{{Cite pmid|15537337}}</ref><ref>{{Cite pmid|16335921}}</ref>
* [[4-Fluoromeperidine]] and other meperidine analogues.<ref name=Lomenzo>{{cite pmid|15743177}}</ref>
* NET selective.<ref>{{Cite pmid|16621532}}</ref><ref>{{Cite pmid|16871320}}</ref>
* Computer.<ref name="Cite pmid|15566285"/><ref>{{Cite pmid|17027270}}</ref>

==References==
{{reflist|2}}

{{Stimulants}}
{{Dopaminergics}}

{{DEFAULTSORT:Cpca}}
[[Category:Stimulants]]
[[Category:Organochlorides]]
[[Category:Piperidines]]
[[Category:Carboxylate esters]]
[[Category:2Fix]]