Vanoxerine

Vanoxerine
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Systematic (IUPAC) name
	1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine
Legal status
Legal status	Investigational New Medicine;
Pharmacokinetic data
Biological half-life	6 hours approx
Identifiers
CAS Number	67469-78-7
ATC code	none
PubChem	CID 3455
Chemical data
Formula	C28H32F2N2O
Molar mass	450.563 g/mol (freebase); 523.494 g/mol (dihydrochloride)[[Script error: No such module "String".]]

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Vanoxerine (GBR-12909) is a piperazine derivative which is a potent and selective DRI. GBR-12909 binds to the target site on the DAT ~ 500 times more strongly than cocaine,^{[citation needed]} but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects.^[1]

Vanoxerine has been researched for use in treating cocaine dependence both as a substitute for cocaine and to block the rewarding effects. This strategy of using a competing agonist with a longer half-life has been successfully used to treat addiction to opiates such as heroin by substituting with methadone. It was hoped that vanoxerine would be of similar use in treating cocaine addiction.^[2]^[3]

Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptors,^[4] and it has also been shown to reduce the consumption of alcohol in animal models of alcohol abuse.^[5]

Vanoxerine has been through human trials up to Phase II,^[6]^[7]^[8] but development was halted after it was shown to cause long QT syndrome.^[9]

However, GBR 12909 has not yet been completely abandoned and it appears hopeful new analogs are "around the corner".^[10]^[11]

As an example, GBR compounds are piperazine based and contain a proximal and a distal nitrogen. It was found that piperidine analogs are still fully active DRIs, although they dont have any affinity for the "piperazine binding site" unlike the GBR compounds. Further SAR revealed that while there is 4 atoms connecting the two fluorophenyl rings to the piperazine, the ether in the chain could be omitted in exchange for a tertiary nitrogen.

References

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de:Vanoxerin

↑ Singh S. Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Chemistry Reviews, 2000. 100(3): 925-1024.
↑ Vetulani J. Drug addiction. Part III. Pharmacotherapy of addiction. Polish Journal of Pharmacology. 2001 Sep-Oct;53(5):415-34.
↑ Preti A. New developments in the pharmacotherapy of cocaine abuse. Addiction Biology. 2007 Jun;12(2):133-51.
↑ Szasz BK, Vizi ES, Kiss JP. Nicotinic acetylcholine receptor antagonistic property of the selective dopamine uptake inhibitor, GBR-12909 in rat hippocampal slices. Neuroscience. 2007 Mar 2;145(1):344-9.
↑ Kamdar NK, Miller SA, Syed YM, Bhayana R, Gupta T, Rhodes JS. Acute effects of naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice. Psychopharmacology (Berlin). 2007 Jun;192(2):207-17.
↑ Søgaard U, Michalow J, Butler B; et al. (1990). "A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects". International clinical psychopharmacology. 5 (4): 237–51. doi:10.1097/00004850-199010000-00001. PMID 2150527.
↑ Preti A. Vanoxerine National Institute on Drug Abuse. Current Opinion in Investigational Drugs. 2000 Oct;1(2):241-51.
↑ Gorelick DA, Gardner EL, Xi ZX. Agents in development for the management of cocaine abuse. Drugs. 2004;64(14):1547-73.
↑ Herman BH, Elkashef A, Vocci F. Medications for the treatment of cocaine addiction: Emerging candidates. Drug Discovery Today: Therapeutic Strategies. 2005 Spring;2(1):87-92.
↑ Rothman RB, Baumann MH, Prisinzano TE, Newman AH. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16. PMID 17897630
↑ Runyon SP, Carroll FI. Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem. 2006;6(17):1825-43. PMID 17017960

[1] Singh S. Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Chemistry Reviews, 2000. 100(3): 925-1024.

[2] Vetulani J. Drug addiction. Part III. Pharmacotherapy of addiction. Polish Journal of Pharmacology. 2001 Sep-Oct;53(5):415-34.

[3] Preti A. New developments in the pharmacotherapy of cocaine abuse. Addiction Biology. 2007 Jun;12(2):133-51.

[4] Szasz BK, Vizi ES, Kiss JP. Nicotinic acetylcholine receptor antagonistic property of the selective dopamine uptake inhibitor, GBR-12909 in rat hippocampal slices. Neuroscience. 2007 Mar 2;145(1):344-9.

[5] Kamdar NK, Miller SA, Syed YM, Bhayana R, Gupta T, Rhodes JS. Acute effects of naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice. Psychopharmacology (Berlin). 2007 Jun;192(2):207-17.

[6] Søgaard U, Michalow J, Butler B; et al. (1990). "A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects". International clinical psychopharmacology. 5 (4): 237–51. doi:10.1097/00004850-199010000-00001. PMID 2150527.

[7] Preti A. Vanoxerine National Institute on Drug Abuse. Current Opinion in Investigational Drugs. 2000 Oct;1(2):241-51.

[8] Gorelick DA, Gardner EL, Xi ZX. Agents in development for the management of cocaine abuse. Drugs. 2004;64(14):1547-73.

[9] Herman BH, Elkashef A, Vocci F. Medications for the treatment of cocaine addiction: Emerging candidates. Drug Discovery Today: Therapeutic Strategies. 2005 Spring;2(1):87-92.

[10] Rothman RB, Baumann MH, Prisinzano TE, Newman AH. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16. PMID 17897630

[11] Runyon SP, Carroll FI. Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem. 2006;6(17):1825-43. PMID 17017960

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Piperazines	2C-B-BZP • BZP • CM156 • DBL-583 • GBR-12783 • GBR-12935 • GBR-13069 • GBR-13098 • GBR-13119 • MeOPP • MBZP • Vanoxerine
Piperidines	1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine • 2-Benzylpiperidine • 3,4-Dichloromethylphenidate • 4-Benzylpiperidine • 4-Methylmethylphenidate • Desoxypipradrol • Difemetorex • Diphenylpyraline • Ethylphenidate • Methylnaphthidate • Methylphenidate (Dexmethylphenidate) • Nocaine • Phacetoperane • Pipradrol • SCH-5472
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Xanthines	Aminophylline • Caffeine • Dimethazan • Paraxanthine • Theobromine • Theophylline
Others	1-(Thiophen-2-yl)-2-aminopropane • 2-Amino-1,2-dihydronaphthalene • 2-Aminoindane • 2-Aminotetralin • 2-Diphenylmethylpyrrolidine • 2-MDP • 3,3-Diphenylcyclobutanamine • 5-(2-Aminopropyl)indole • 5-Iodo-2-aminoindane • AL-1095 • Amfonelic acid • Amineptine • Amiphenazole • Atipamezole • Bemegride • Benzydamine • BTQ • BTS 74,398 • Carphedon • Ciclazindol • Cilobamine • Clofenciclan • Cropropamide • Crotetamide • Diclofensine • Dimethocaine • Diphenylprolinol • Efaroxan • Etamivan • EXP-561 • Fenpentadiol • Feprosidnine • Gamfexine • Gilutensin • GYKI-52895 • Hexacyclonate • Idazoxan • Indanorex • Indatraline • JNJ-7925476 • JZ-IV-10 • Lazabemide • Leptacline • Levopropylhexedrine • LR-5182 • Mazindol • Meclofenoxate • Medifoxamine • Mefexamide • Mesocarb • Nefopam • Nikethamide • Nomifensine • O-2172 • Oxaprotiline • Phthalimidopropiophenone • PNU-99,194 • Propylhexedrine • PRC200-SS • Rasagiline • Rauwolscine • Rubidium chloride • Setazindol • Tametraline • Tandamine • Trazium • UH-232 • Yohimbine
See also Sympathomimetic amines

v t e Piperazines
Simple piperazines (no additional rings)	1-Cyclohexylpiperazine • Aminoethylpiperazine • Diethylcarbamazine • HEPPS • Midafotel • Piperazine • PIPES
Phenylpiperazines	Acaprazine • Antrafenine • Aripiprazole • Batoprazine • Bifeprunox • BRL-15,572 • Ciprofloxacin • CSP-2503 • Dapiprazole • DCPP • DMPP • Dropropizine • EGIS-12,233 • Elopiprazole • Eltoprazine • Enpiprazole • Ensaculin • Etoperidone • Flesinoxan • Flibanserin • Fluprazine • Itraconazole • Ketoconazole • Levodropropizine • Lorpiprazole • mCPP • MeOPP • Mepiprazole • Naftopidil • Naphthylpiperazine • Nefazodone • Niaprazine • Oxypertine • Pardoprunox • pCPP • pFPP • Posaconazole • PRX-00023 • S-14,506 • S-14,671 • S-15,535 • SB-258,585 • SB-271,046 • SB-357,134 • SB-399,885 • Sonepiprazole • TFMPP • Tolpiprazole • Trazodone • Urapidil • Vesnarinone • Vilazodone • WAY-100,135 • WAY-100,635
Benzylpiperazines	2C-B-BZP • Befuraline • Bifeprunox • Buclizine • BZP • Chlorbenzoxamine • DBZP • Fipexide • Imatinib • MBZP • MDBZP • Meclozine • Piberaline • Piribedil • Trimetazidine • Vesnarinone
Diphenylalkylpiperazines (benzhydrylalkylpiperazines)	Almitrine • Amperozide • BRL-15,572 • Buclizine • BW373U86 • Cetirizine • Chlorbenzoxamine • Chlorcyclizine • Cinnarizine • Clocinizine • Cyclizine • DBL-583 • Diphenylmethylpiperazine • Dotarizine • DPI-221 • DPI-287 • DPI-3290 • GBR-12,783 • GBR-12,935 • GBR-13,069 • GBR-13,098 • GBR-13,119 • Hydroxyzine • Lidoflazine • Manidipine • Meclozine • Oxatomide • SNC-80 • Vanoxerine
Pyrimidinylpiperazines	Buspirone • Dasatinib • Eptapirone • Gepirone • Ipsapirone • Piribedil • Pyrimidinylpiperazine • Revospirone • Tandospirone • Tirilazad • Trimazosin • Umespirone • Zalospirone
Pyridinylpiperazines	Atevirdine • Azaperone • Pyridinylpiperazine
Benzo(iso)thiazolyl piperazines	Lurasidone • Perospirone • Revospirone • Tiospirone • Ziprasidone
Tricyclics (piperazine attached via side chain)	Amoxapine • Clopenthixol • Clozapine • Flupentixol • Fluphenazine • Loxapine • Olanzapine • Opipramol • Perazine • Perphenazine • Pirenzepine • Prochlorperazine • Thiethylperazine • Thiothixene • Trifluoperazine • Zuclopenthixol
Others	6-Nitroquipazine • Azimilide • Cinepazet • Cyclohexylpiperazine • Hexocyclium • Indinavir • JNJ-7777120 • Lodenafil • Mirodenafil • PB-28 • Quipazine • Ranolazine • SA-4503 • Sildenafil • Tadalafil • Vardenafil • VUF-6002 • Zipeprol

Vanoxerine

See also

References

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