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(+)-CPCA

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(+)-CPCA
File:Nocaine.png
Clinical data
ATC code
  • none
Identifiers
  • methyl (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H18ClNO2
Molar mass267.751 g/mol g·mol−1
3D model (JSmol)
  • COC(=O)C1CN(C)CCC1c(cc2)ccc2Cl

(+)-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.[1] This compound was first developed as a substitute agent for cocaine.

Since this time a large number of substituted phenylpiperidine 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.

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.

Routes of synthesis

To make any of the phenyltropanes requires either a source of cocaine, or extensive and repeated seperation 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.[2]

Laboratory synthesis has been devised 5736556 but is hampered by the fact that in addition to the wanted isomer of anhydroecgonidine, they are also saddled with the unwanted enantiomer.

The unwanted isomer can of course be separated although usually this step is omitted.

Semi-synthetic production of nocaine uses arecoline as precursor (this is not "illegal" to buy).

A necessary step in the production of phenyltropanes is ecgonine → ecgonidine.

The last step in the biosynthesis of cocaine is benzoylation of methylecgonine by the coca plant.[citation needed]

If the enzyme that is held accountable for the last step can be disabled, a more direct route to the phenyltropanes can be effected.

This pattern of logic was used to make designer antibiotics.

SAR to troparil

Troparil is already a moderately active psychostimulant reported to have 4 times the potency of cocaine.[3]

In the case of nocaine, absence of a chlorine atom means that all DRI potency is lost.

Activity at other targets such as the SERT is still possible.

Locomotor activation

Apparently locomotor activity (LMA) consists of 2 components: one is the property of ambulation or forward movement, whereas the other is called stereotypy.[citation needed]

In contrast to tropane based analogs such as RTI-31, all nocaine cocaine analogs made out of arecoline (regardless of stereochemistry or para-substitution) were poor at causing ambulation.[4][5]

Interestingly, the nocaine compounds that were tested are more potent than cocaine at effecting stereotypy by an order of magnitude that is roughly congruent with their increased affinity for the DAT.

It would still be presumptous at his stage to say what the reasons for this are, although residual activity at mu-opioid receptors was cited as one of the possible explanations.[6]

Self administration

In the case of (RS)-CPCA, the carbomethoxy ester has been intentionally epimerized, even though this leads to a drop in potency.

IC50 (nM)
Compound [3H]N [3H]S [3H]D
Cocaine119177275
(SS)-CPCA9839067
(RS)-CPCA905,900276
  • (–)-cis-CPCA was so much more likely than (+)-CPCA to be self-administered reliably.[4][5]

[7]

It has some stimulant effects, but is only around one quarter to one third the potency of cocaine, and cocaine-addicted animals self administer it less often than cocaine.[4]

It also blocks the action of cocaine when the two drugs are administered at the same time, and does not increase cocaine-induced convulsions.[5] 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.

Effect of N-modification and ester replacement

(+)-CPCA was N-demethylated, the ester was reduced, or both.[8][9]

File:Oxadiazole.gif
oxadiazole
N-demethylating RS nocaine and derivatives
R [3H]N [3H]D [3H]S
CO2Me252 (Accurate?) → 7.9233 → 2798,490 → 434
CH2OH198 → 69497 → 8361,550 → 239
Oxadiazole256 → 34187 → 1895,960 → 373
  • Convulsions occured at the highest dose tested, in the case of Nor-(+)-CPCA.
  • Unexpectedly, Nor-(+)-CPCA had an increased duration span, although was also an unreliable behavioral enhancer.
  • The alcohol is a more reliable SERT blocker than either the ester or the oxadiazole.

Both the alcohol and the oxadiazole had increased duration relative to the ester, although the alcohol had a delayed onset of action.

(+)-CPCA side-chain modifcation

It is unclear to what extent (+)-CPCA is an acceptable drug in its own right (c.f. Paxil). Alot of effort has been made into exploring further reactions of the methoxycarbonyl in (+)-CPCA.

MAT Activity of some (+)-CPCA derivatives
3 Position [3H]D [3H]S [3H]N CLogP MW
COOMe2338,4902523.22268
CONMe2[10]2,14018,9005692.77281
CH2OAc5999012352.98282
CH2OCH2CH=CH260231203.38280
CH2COOEt791911013.34296
CH2CONMe2161,994462.80295
CH2CH2COOMe68255313.34296
trans CH=CHCO2Me535012723.42294
CH2CH2CH3202286.54.91252
CH2CH2CH2OH162,8105643.09268
  • Replacing the -CO2Me in (+)-CPCA with -CH2CO2Et afforded improved activity and was an active TRI.[10]

An attempt to overlay the above compound onto (–)-cis-CPCA should show the similarity.

See also

References

  1. ^ Kozikowski AP, Araldi GL, Boja J, Meil WM, Johnson KM, Flippen-Anderson JL, George C, Saiah E. Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton. Journal of Medicinal Chemistry. 1998 May 21;41(11):1962-9. PMID 9599245
  2. ^ Clarke RL, Daum SJ, Gambino AJ, Aceto MD, Pearl J, Levitt M, Cumiskey WR, Bogado EF. Compounds affecting the central nervous system. 4. 3 Beta-phenyltropane-2-carboxylic esters and analogs. Journal of Medicinal Chemistry. 1973 Nov;16(11):1260-7. PMID 4747968
  3. ^ Runyon SP, Carroll FI. Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem. 2006;6(17):1825-43. PMID 17017960
  4. ^ a b c Woolverton WL, Ranaldi R, Wang Z, Ordway GA, Paul IA, Petukhov P, Kozikowski A. Reinforcing strength of a novel dopamine transporter ligand: pharmacodynamic and pharmacokinetic mechanisms. Journal of Pharmacology and Experimental Therapeutics. 2002 Oct;303(1):211-7. PMID 12235253
  5. ^ a b c Kozikowski AP, Johnson KM, Deschaux O, Bandyopadhyay BC, Araldi GL, Carmona G, Munzar P, Smith MP, Balster RL, Beardsley PM, Tella SR. Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine. Journal of Pharmacology and Experimental Therapeutics. 2003 Apr;305(1):143-50. PMID 12649362
  6. ^ a b Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML. Synthesis and biological evaluation of meperidine analogues at monoamine transporters. Journal of Medicinal Chemistry. 2005 Mar 10;48(5):1336-43. PMID 15743177
  7. ^ Trzcińska M, Pimentel P, Stellar JR, Hanson RN, Choi SW, Elmaleh DR, Zhang J, Prakash KR, Tamiz AP, Kozikowski AP, Johnson KM, Smith MP, Babich JW. Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward. Pharmacology, Biochemistry and Behaviour. 2001 Jan;68(1):171-80. PMID 11274722
  8. ^ Petukhov PA, Zhang M, Johnson KJ, Tella SR, Kozikowski AP. SAR studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles. Bioorganic and Medicinal Chemistry Letters. 2001 Aug 20;11(16):2079-83. PMID 11514143
  9. ^ Petukhov PA, Zhang J, Kozikowski AP, Wang CZ, Ye YP, Johnson KM, Tella SR. SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement. Journal of Medicinal Chemistry. 2002 Jul 18;45(15):3161-70. PMID 12109901
  10. ^ a b Petukhov PA, Zhang J, Wang CZ, Ye YP, Johnson KM, Kozikowski AP. 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 of Medicinal Chemistry. 2004 Jun 3;47(12):3009-18. PMID 15163183
  11. ^ Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski AP. Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors. Journal of Medicinal Chemistry. 2000 Mar 23;43(6):1215-22. PMID 10737754
  12. ^ Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP. Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. Journal of Medicinal Chemistry. 2004 Nov 18;47(24):5821-4. PMID 15537337
  13. ^ He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP. 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 of Medicinal Chemistry. 2005 Dec 15;48(25):7970-9. PMID 16335921
  14. ^ Musachio JL, Hong J, Ichise M, Seneca N, Brown AK, Liow JS, Halldin C, Innis RB, Pike VW, He R, Zhou J, Kozikowski AP. Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors. Bioorganic and Medicinal Chemistry Letters. 2006 Jun 15;16(12):3101-4. PMID 16621532
  15. ^ Zhou J. Norepinephrine transporter inhibitors and their therapeutic potential. Drugs of the Future. 2004 Dec;29(12):1235-1244. PMID 16871320
  16. ^ Yuan H, Kozikowski AP, Petukhov PA. 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 of Medicinal Chemistry. 2004 Dec 2;47(25):6137-43. PMID 15566285
  17. ^ Yuan H, Petukhov PA. Improved 3D-QSAR CoMFA of the dopamine transporter blockers with multiple conformations using the genetic algorithm. Bioorg Med Chem Lett. 2006 Dec 15;16(24):6267-72. PMID 17027270
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