Nocaine

Drugbox
IUPAC_name = methyl (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate


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PubChem= 10333222
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C=14 | H=18 | Cl=1 | N=1 | O=2
molecular_weight = 267.751 g/mol
smiles = COC(=O)C1CN(C)CCC1c(cc2)ccc2Cl
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Nocaine ((+)-CPCA, 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 and with inverted stereochemistry around the carbomethoxy group. It was developed in the late 1990s, [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] and 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. [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] [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] [Zhou J. Norepinephrine transporter inhibitors and their therapeutic potential. "Drugs of the Future". 2004 Dec;29(12):1235-1244. PMID 16871320] [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]

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. [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] 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. [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] It also blocks the action of cocaine when the two drugs are administered at the same time, and does not increase cocaine-induced convulsions. [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] This is a significant field of research with much work ongoing, [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] [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] [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] [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] [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] [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] and dozens of novel compounds have been developed although none have yet come to market.

References

Patents

* [http://www.google.com/patents?id=veMFAAAAEBAJ&dq=6180648 Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6180648, 2001.]
* [http://www.google.com/patents?id=iSQLAAAAEBAJ&dq=6376673 United States Patent 6376673 Moldt, et al.]
* [http://www.google.com/patents?id=Jh8AAAAAEBAJ&dq=6472422 Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6472422, 2002.]
* [http://www.google.com/patents?id=3iURAAAAEBAJ&dq=6806281 Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, US6806281, 2004.]
* Kozikowski; Alan P.; Araldi; Gian Luca, Analogs of cocaine, WO9845263, 1998.
* Kozikowski; Alan P.; Araldi; Gian Luca; Tamiz; Amir P., WO0020390, 2000.
* WO2004039778 Date: 2004-05-13 Inventor: WAETJEN FRANK (DK) Applicant: NEUROSEARCH AS (DK); WAETJEN FRANK (DK)
* KOZIKOWSKI ALAN P (US); ZHOU JIA (US), WO2005041875, 2005.
* KOZIKOWSKI ALAN P (US); ZHOU JIA (US); EP1680113, 2006-07-19; UNIV GEORGETOWN (US)