The AAPS Journal

, Volume 8, Issue 4, pp E682–E692 | Cite as

Vesicular monoamine transporter 2: Role as a novel target for drug development

  • Guangrong Zheng
  • Linda P. Dwoskin
  • Peter A. Crooks


In the central nervous, system, vesicular monoamine transporter 2 (VMAT2) is the only transporter that moves cytoplasmic dopamine (DA) into synaptic vesicles for storage and subsequent exocytotic release. Pharmacologically enhancing DA sequenstration by VMAT2, and thus preventing the oxidation of DA in the cytoplasm, may be a strategy for treating diseases such as Parkinson's disease. VMAT2 may also be a novel target for the development of treatments for psychostimulant abuse. This review summarizes the possible role of VMAT2 as a therapeutic target, VMAT2 ligands reported in the literature, and the structure-activity relationship of these ligands, including tetrabenazine analogs, ketanserin analogs, lobeline analogs, and 3-amine-2-phenylpropene analogs. The molecular structure of VMAT2 and its relevance to ligand binding are briefly discussed.


vesicular monoamine transporter 2 Parkinson's disease psychostimulant abuse tetrabenazine ketanserin lobeline 


  1. 1.
    Yelin R, Schuldiner S. Vesicular neurotransmitter transporters: pharmacology, biochemistry, and molecular analysis. In: Reith MEA, ed Neurotransmitter Transporters: Structure, Function, and Regulation 2nd Totowa, NJ: Humana Press; 2002:313–354.Google Scholar
  2. 2.
    Erickson JD, Eiden LE, Hoffiman BJ. Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci USA. 1992;89:10993–10997.PubMedGoogle Scholar
  3. 3.
    Lin Y, Peter D, Roghani A, et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell. 1992;70:539–551.Google Scholar
  4. 4.
    Erickson J, Eiden L. Functional identification and molecular cloning of a human brain vesicle monoamine transporter. J Neurochem. 1993, 61:2314–2317.PubMedGoogle Scholar
  5. 5.
    Erickson JD, Schaefer MKH, Bonner TI, Eiden LE, Weihe E. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci USA. 1996;93:5166–5171.PubMedGoogle Scholar
  6. 6.
    Peter D, Liu Y, Sternini C, de Giorgio R, Brecha N, Edwards RH. Differential expression of two vesicular monoamine transporters. J Neurosci. 1995;15:6179–6188.PubMedGoogle Scholar
  7. 7.
    Weihe E, Schafer MK, Erickson JD, Eiden LE. Localization of vesicular monoamine transporter isoforms (VMAT1 and VMAT2) to endocrine cells and neurons in rat. J Mol Neurosci. 1994;5:149–164.PubMedGoogle Scholar
  8. 8.
    Hansson SR, Mezey E, Hoffman BJ. Ontogeny of vesicular monoamine transporter mRNAs VMAT1 and VMAT2, II: expression in neural creast derivatives and their target sites in the rat. Brain Res Dev Brain Res. 1998;110:159–174.PubMedGoogle Scholar
  9. 9.
    Peter D, Jimenez J, Lin Y, Kim J, Edwards RH. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J Biol Chem. 1994;269:7231–7237.PubMedGoogle Scholar
  10. 10.
    Pletscher A. Effect of neuroleptics and other drugs on monoamine uptake by membranes of adrenal chromaffin granules. Br J Pharmacol. 1977;59:419–424.PubMedGoogle Scholar
  11. 11.
    Scherman D, Henry JP. Reserpine binding to bovine chromaffin granule membranes. Mol Pharmacol. 1984;25:113–122.PubMedGoogle Scholar
  12. 12.
    Darchen F, Scherman D, Henry JP. Reserpine binding to chromaffin granules suggests the existence of two conformations of the monoamine transporter. Biochemistry. 1989;28:1692–1697.PubMedGoogle Scholar
  13. 13.
    Henry JP, Scherman D. Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles. Biochem Pharmacol. 1989;38:2395–2404.PubMedGoogle Scholar
  14. 14.
    Scherman D, Jaudon P, Henry JP. Characterization of the monoamine carrier of chromaffin granule membrane by binding of [2–3H]dihydrotetrabenazine. Proc Natl Acad Sci USA. 1983;80:584–588.PubMedGoogle Scholar
  15. 15.
    Cohen G, Kesler N. Monoamine oxidase and mitochondrial respiration. J Neurochem. 1999;73:2310–2315.PubMedGoogle Scholar
  16. 16.
    Lin Y, Edwards RH. The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci. 1997;20:125–156.Google Scholar
  17. 17.
    Langston JW. The etiology of Parkinson's disease with emphasis on the MPTP story. Neurology, 1996;47:S153-S160.PubMedGoogle Scholar
  18. 18.
    Snyder SH, D'Amato RJ. MPTP: a neurotoxin relevant to the pathophysiology of Parkinson's disease. Neurology. 1986:36:250–258.PubMedGoogle Scholar
  19. 19.
    Jenner P, Schapira AHV, Marsden CD. New insights into the cause of Parkinson's disease. Neurology. 1992;42:2241–2250.PubMedGoogle Scholar
  20. 20.
    Jenner P, Dexter DT, Sian J, Schapira AHV, Marsden CD. Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. Ann Neurol. 1992;32:S82-S87.PubMedGoogle Scholar
  21. 21.
    German DC, Sonsalla PK. A role for the vesicular monoamine transporter (VMAT2) in Parkinson's disease. Adv Behav Biol. 2003;54:131–137.Google Scholar
  22. 22.
    Adams JD, Jr, Chang ML, Klaidman L. Parkinson's disease—redox mechanisms. Curr Med Chem. 2001;8:809–814.PubMedGoogle Scholar
  23. 23.
    Scherman D, Darchen F, Desnos C, Henry JP. 1-Methyl-4-phenylpyridinium is a substrate of the vesicular monoamine uptake system of chromaffin granules. Eur J Pharmacol. 1988:146:359–360.PubMedGoogle Scholar
  24. 24.
    Daniels AJ, Jr, Reinhard JF, Jr. Energy-driven uptake of the neurotoxin 1-methyl-4-phenylpyridine into chromaffin granules via the catecholamine transporter. J Biol Chem. 1988;263:5034–5036.PubMedGoogle Scholar
  25. 25.
    Darchen F, Scherman D, Henry JP. Characteristics of the transport of quaternary ammonium 1-methyl-4-phenylpyridine by chromaffin granules. Biochem Pharmacol. 1988;37:4381–4387.PubMedGoogle Scholar
  26. 26.
    Del Zompo M, Piccardi MP, Ruiu S, Quartu M, Gessa GL, Vaccari A. Selective MMP+ uptake into synaptic dopamine vesicles: possible involvement in MPTP neurotoxicity. Br J Pharmacol. 1993;109:411–414.PubMedGoogle Scholar
  27. 27.
    Moriyama Y, Amakatsu K, Futai M. Uptake of the neurotoxin, 4-methylphenylpyridinium, into chromaffin granules and synpatic vesicles: a proton gradient, drives its uptake through monoamine transporter. Arch Biochem Biophys. 1993:305:271–277.PubMedGoogle Scholar
  28. 28.
    Takahashi N, Miner LL, Sora I, et al. VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci USA. 1997;94:9938–9943.PubMedGoogle Scholar
  29. 29.
    Speciale SG, Liang CL, Sonsalla PK, Edwards RH, German DC, The neurotoxin 1-methyl-4-phenylpyridinium is sequestered within neurons that contain the vesicular monoamine transporter. Neuroscience. 1998;84:1177–1185.PubMedGoogle Scholar
  30. 30.
    Gainetdinov RR, Fumagalli F, Wang YM, et al.. Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice. J Neurochem. 1998;70:1973–1978.PubMedGoogle Scholar
  31. 31.
    German DC, Liang CL, Manaye KF, Lane K, Sonsalla PK. Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic, neurons, but not locus coeruleus noradrenergic neurons. Neuroscience. 2000;101:1063–1069.PubMedGoogle Scholar
  32. 32.
    Staal RGW, Sonsalla PK. Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. J Pharmacol Exp Ther. 2000;293:336–342.PubMedGoogle Scholar
  33. 33.
    Mooslehner KA, Chan PM, Xu W, et al. Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism. Mol Cell Biol. 2001;21:5321–5331.PubMedGoogle Scholar
  34. 34.
    Fumagalli F, Gainetdinov RR, Wang, YM, Valenzano KJ, Miller GW, Caron MG. Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice. J Neurosci. 1999;19:2424–2431.PubMedGoogle Scholar
  35. 35.
    Kariya S, Takahashi N, Hirano M, Ueno S. Increased vulnerability to L-DOPA toxicity in dopaminergic neurons from VMAT2 heterozygote knockout mice. J Mol Neurosci. 2005;27:277–280.PubMedGoogle Scholar
  36. 36.
    Glatt CE, Wahner AD, White DJ, Ruiz-Linares A, Ritz B, Gain-of-function haplotypes in the vesicular monoamine transporter prom oter are protective for Parkinson disease in women. Hum Mol Genet. 2005;15:299–305.PubMedGoogle Scholar
  37. 37.
    Sandoval V, Riddle EL, Hanson GR, Fleckenstein AE. Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits. J Pharmacol Exp Ther. 2002:304:1181–1187.Google Scholar
  38. 38.
    Hanson GR, Sandoval V, Riddle E, Fleckenstein AE. Psychostimulants and vesicle trafficking: a novel mechanism and therapeutic implications. Ann NY Acad Sci.. 2004;1025:146–150.PubMedGoogle Scholar
  39. 39.
    Hall ED, Andrus PK, Oostveen JA, Althaus JS, Von Voigtlander PF. Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons. Brain Res. 1996;742:80–88.PubMedGoogle Scholar
  40. 40.
    Sethy VH, Wu H, Oostveen JA, Hall ED. Neuroprotective effects of the dopamine agonist pramipexole and bromocriptine in 3-acetylpyridine-treated rats. Brain Res. 1997;754:181–186.PubMedGoogle Scholar
  41. 41.
    Truong JG, Rau KS, Hanson GR, Fleckenstein AE. Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson's neurodegeneration. Eur J Pharmacol 2003;474:223–226.PubMedGoogle Scholar
  42. 42.
    Truong JG, Hanson GR, Fleckenstein AE. Apomorphine increases vesicular monoamine transporter-2 function: implications for neurodegeneration. Eur J Pharmacol. 2004;492:143–147.PubMedGoogle Scholar
  43. 43.
    Amara SG, Sonders MS. Neurotransmitter transporters as molecular targets for addictive drugs Drug Alcohol Depend. 1998;51:87–96.PubMedGoogle Scholar
  44. 44.
    Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev. 1987;94:469–492.PubMedGoogle Scholar
  45. 45.
    Koob GF. Neural mechanisms of drug reinforcement. Ann N Y Acad Sci. 1992;654:171–191.PubMedGoogle Scholar
  46. 46.
    Fleckenstein AE, Hanson GR. Impact of psychostimulants on vesicular monoamine transporter function. Eur J Pharmacol. 2003;479:283–289.PubMedGoogle Scholar
  47. 47.
    Riddle EL, Fleckenstein AE, Hanson GR. Role of monoamine transporters in mediating psychostimulant effects. AAPS J. 2005;7:E847-E851 serial online.PubMedGoogle Scholar
  48. 48.
    Brown JM, Hanson GR, Fleckenstein AE. Regulation of the vesicular monoamine transporter-2: a novel mechanism for cocaine and other psychostimulants. J Pharmacol Exp Ther. 2001;296:762–767.PubMedGoogle Scholar
  49. 49.
    Sulzer D, Maidment NT, Rayport S. Amphetamine and other weak bases act to promote reverse transport of dopamine in ventral midbrain neurons. J Neurochem. 1993;60:527–535.PubMedGoogle Scholar
  50. 50.
    Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci. 1995;15:4102–4108.PubMedGoogle Scholar
  51. 51.
    Johnson RG. Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport. Physiol Rev. 1988;68:232–307.PubMedGoogle Scholar
  52. 52.
    Sulzer D, Rayport S. Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action. Neuron. 1990;5:797–808.PubMedGoogle Scholar
  53. 53.
    Brown JM, Hanson GR, Fleckenstein AE. Methamphetamine rapidly decreases vesicular dopamine uptake. J Neurochem. 2000;74:2221–2223.PubMedGoogle Scholar
  54. 54.
    Wang Y, Gainetdinov RR, Fumagalli F, et al., Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron. 1997;19:1285–1296.PubMedGoogle Scholar
  55. 55.
    Pletscher A, Brossi A, Gey KF. Benzoquinolizine derivatives: a new class of monoamine decreasing drugs with psychotropic action. Int Rev Neurobiol. 1962;4:275–306.Google Scholar
  56. 56.
    Pettibone DJ, Pflueger AB, Totaro JA. Tetrabenazine-induced depletion of brain monoamines: mechanism by which desmethylimipramine protects cortical norepinephrine. Eur J Pharmacol. 1984;102:431–436.PubMedGoogle Scholar
  57. 57.
    Brossi A, Lindlar H, Walter M, Schnider O. Synthesis in the emetine series, I: 2-oxohydrobenzo[a]quinolizines. Helv Chim Acta. 1958;41:1793–1806.Google Scholar
  58. 58.
    Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurother. 2006;6:7–17.PubMedGoogle Scholar
  59. 59.
    Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease. Neurology. 2006;66:366–372.Google Scholar
  60. 60.
    Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology. 1997;48:358–362.PubMedGoogle Scholar
  61. 61.
    Reches A, Burke RE, Kuhn CM, Hassan MN, Jackson VR, Fahn S. Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain. J Pharmacol Exp Ther. 1983;225:515–521.PubMedGoogle Scholar
  62. 62.
    DaSilva JN, Kilbourn MR, Mangner TJ. Synthesis of [11C]tetrabenazine a vesicular monoamine uptake inhibitor, for PET imaging studies. Appl Radiat Isot. 1993;44:673–676.PubMedGoogle Scholar
  63. 63.
    Kilbourn MR, DaSilva JN, Frey KA, Koeppe RA, Kuhl DE. In vivo imaging of vesicular monoamine transporters in human brain using [11C]tetrabenazine and positron emission tomography. J Neurochem. 1993;60:2315–2318.PubMedGoogle Scholar
  64. 64.
    DaSilva JN, Kilbourn MR, Domino EF. In vivo imaging of monoaminergic nerve terminals in normal and MPTP-lesioned primate brain using positron emission tomography (PET) and [11C]tetrabenazine. Synapse. 1993;14:128–131.PubMedGoogle Scholar
  65. 65.
    DaSilva JN, Carey JE, Sherman PS, Pisani TJ, Kilbourn MR. Characterization of [11C]tetrabenazine as an in vivo radioligand for the vesicular monoamine transporter. Nucl Med Biol. 1994;21:151–156.PubMedGoogle Scholar
  66. 66.
    Kilbourn MR. PET radioligands for vesicular neurotransmitter transporters. Med Chem Res. 1994;5:113–126.Google Scholar
  67. 67.
    Schwartz DE, Bruderer H, Rieder J, Brossi A. Metabolic studies of tetrabenazine, a psychotropic drug in animals and man. Biochem Pharmacol. 1966;15:645–655.PubMedGoogle Scholar
  68. 68.
    Scherman D, Raisman R, Ploska A, Agid Y. [3H]Dihydrotetrabenazine, a new in vitro monoaminergic probe for human brain. J Neurochem. 1988;50:1131–1136.PubMedGoogle Scholar
  69. 69.
    Masuo Y, Pelaprat D, Scherman D, Rostene W. [3H]Dihydrotetrabenazine, a new marker for the visualization of dopaminergic denervation in the rat striatum. Neurosci Lett. 1990;114:45–50.PubMedGoogle Scholar
  70. 70.
    Zucker M, Weizman A, Rehavi M. Characterization of high-affinity [3H]TBZOH binding to the human platelet vesicular monoamine transporter. Life Sci. 2001;69:2311–2317.PubMedGoogle Scholar
  71. 71.
    Jewett DM, Kilbourn MR, Lee LC. A simple synthesis of[11C]dihydrotetrabenazine (DTBZ). Nucl Med Biol. 1997;24:197–199.PubMedGoogle Scholar
  72. 72.
    Koeppe RA, Frey KA, Kume A, Albin R, Kilbourn MR, Kuhl DE. Equilibrium versus compartmental analysis for assessment of the vesicular monoamine transporter using (+)-[11C]dihydrotetrabenazine (DTBZ) and positron emission tomography. J Cereb Blood Flow Metab. 1997;17:919–931.PubMedGoogle Scholar
  73. 73.
    DaSilva JN, Kilbourn MR, Mangner TJ. Synthesis of a [11C]methoxy derivative of alpha-dihydrotetrabenazine: a radioligand for studying the vesicular monoamine transporter. Appl Radiat Isot. 1993;44:1487–1489.PubMedGoogle Scholar
  74. 74.
    Kilbourn MR, Lee LC, Heeg MJ, Jewett DM. Absolute configuration of (+)-dihydrotetrabenazine, an active metabolite of tetrabenazine. Chirality. 1997;9:59–62.PubMedGoogle Scholar
  75. 75.
    Kilbourn MR, Lee L, Vander Borght T, Jewett D, Frey K. Binding of alpha-dihydrotetrabenazine to the vesicular monoamine transporter is stereospecific. Eur J Pharmacol. 1995;278:249–252.PubMedGoogle Scholar
  76. 76.
    Kilbourn MR, Lee LC, Jewett DM, Vander Borght TM, Koeppe RA, Frey KA. In vitro and in vivo binding of α-dihydrotetrabenazine to the vesicular monoamine transporters is stereospecific. J Cereb Blood Flow Metab. 1995;15:S650.Google Scholar
  77. 77.
    Clarke I, Turtle R, Johnston G, inventors. Cambridge Laboratories Limited, UK, assignee. Preparation of dihydrotetrabenazines with affinity for monoamine transporters for use in pharmaceutical compositions for the treatment of hyperkinetic disorders. WO 2 005 077 946. February 11, 2005.Google Scholar
  78. 78.
    Tridgett R, Clarke I, Turtle R, Johnston G, inventors. Cambridge Laboratories Limited, UK, assignee. Preparation of dihydrotetrabenazine isomers for the treatment of hyperkinetic movement disorders. GB 2 410 947. February 11, 2004.Google Scholar
  79. 79.
    Vander Borght TM, Sima AAF, Kilbourn MR, Desmond TJ, Kuhl DE, Frey KA. [3H]Methoxytetrabenazine: a high specific activity ligand for estimating monoaminergic neuronal integrity. Neuroscience. 1995;68:955–962.Google Scholar
  80. 80.
    Vander Borght TM, Kilbourn MR, Koeppe RA, et al. In vivo imaging of the brain vesicular monoamine transporter. J Nucl Med. 1995;36:2252–2260.Google Scholar
  81. 81.
    Kilbourn MR, Sherman PS, Abbott LC. Mutant mouse strains as models for in vivo radiotracer evaluations: [11C]methoxytetrabenazine ([11C]MTBZ) in tottering mice. Nucl Med Biol. 1995;22:565–567.PubMedGoogle Scholar
  82. 82.
    F. Hoffmann-La Roche & Co inventor. F. Hoffmann-La Roche & Co, assignee. Substituted 2-hydroxy-1,2,3,4,6,7-hexahydrobenzo[a]quin olizines and their salts. GB 839 105. June 29, 1960.Google Scholar
  83. 83.
    F. Hoffmann-La Roche & Co. inventor. F. Hoffmann-La Roche & Co, assignee. Benzo[a]quinolizine derivatives. BE 633 559. December 13, 1963.Google Scholar
  84. 84.
    F. Hoffmann-La Roche & Co. inventor. F. Hoffmann-La Roche & Co, assignee. Substituted tetrahydrobenzo[a]quinolizines. BE 636 798. March 2, 1964.Google Scholar
  85. 85.
    Lee LC, Vander Borght T, Sherman PS, Frey KA, Kilbourn MR. In vitro and in vivo studies of benzoisoquinoline ligands for the brain synaptic vesicle monoamine transporter. J Med Chem. 1996;39:191–196.PubMedGoogle Scholar
  86. 86.
    Canney DJ, Guo YZ, Kung MP, Kung HF. Synthesis and preliminary evaluation of an iodovinyl-tetrabenazine analog as a marker for the vesicular monoamine transporter. J Labelled Compd Radiopharm. 1993;33:355–368.Google Scholar
  87. 87.
    Kung MP, Canney DJ, Frederick D, Zhuang Z, Billings JJ, Kung HF. Binding of 125I-iodovinyltetrabenazine to CNS vesicular monoamine transport sites. Synapse. 1994;18:225–232.PubMedGoogle Scholar
  88. 88.
    Clarke FH, Hill RT, Koo J, et al.. A series of hexahydro[1,4]oxazino [3,4-a]isoquinolines as potential neuroleptics. J Med Chem. 1978;21:785–791.PubMedGoogle Scholar
  89. 89.
    Fahrenholtz KE, Capomaggi A, Lurie M, Goldberg MW, Kierstead RW. Octahydrophenanthrene analogs of tetrabenazine. J Med Chem. 1966;9:304–310.PubMedGoogle Scholar
  90. 90.
    Saner A, Pletscher A. A benzo[a]quinolizine derivative with a neuroleptic-like action on cerebral monoamine turnover. J Pharmacol Exp Ther. 1977;203:556–563.PubMedGoogle Scholar
  91. 91.
    Harnden MR, Short JH. 2-Thio-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizines. J Med Chem. 1967;10:1183–1184.PubMedGoogle Scholar
  92. 92.
    Aranda G, Beaucourt JP, Ponchant M, Isambert MF, Henry JP. Synthesis and biological activity of iodinated and photosensitive derivatives of tetrabenazine. Eur J Med Chem 1990;25:369–374.Google Scholar
  93. 93.
    Scherman D, Gasnier B, Jaudon P, Henry JP. Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter. Mol Pharmacol. 1988;33:72–77.PubMedGoogle Scholar
  94. 94.
    Canney DJ, Kung MP, Kung HF. Amino- and amidotetrabenazine derivatives: synthesis and evaluation as potential ligands for the vesicular monoamine transporter. Nucl Med Biol. 1995;22:527–535.PubMedGoogle Scholar
  95. 95.
    Leysen JE, Niemegeers CJE, Van Nueten JM, Laduron PM. [3H]Ketanserin (R-4-1468), a selective 3H-ligand for serotonin2 receptor binding sites. Binding properties, brain distribution, and functional role. Mol Pharmacol. 1982;21:301–314.PubMedGoogle Scholar
  96. 96.
    Darchen F, Scherman D, Laduron PM, Henry JP. Ketanserin binds to the monoamine transporter of chromaffin granules and of synaptic vesicles. Mol Pharmacol. 1988;33:672–677.PubMedGoogle Scholar
  97. 97.
    Henry JP, Gasnier B, Isambert MF, Darchen F, Scherman D. Ketanserin as a ligand of the vesicular monoamine transporter. Adv Biosci. 1991;82:147–150.Google Scholar
  98. 98.
    Leysen JE, Eens A, Gommeren W, Van Gompel P, Wynants J, Janssen PAJ. Identification of nonserotonergic [3H]ketanserin binding sites associated with nerve terminals in rat brain and with platelets; relation with release of biogenic amine metabolites induced by ketanserin-and tetrabenazine-like drugs. J Pharmacol Exp Ther. 1988;244:310–321.PubMedGoogle Scholar
  99. 99.
    Isambert MF, Gasnier B, Laduron PM, Henry JP. Photoaffinity labeling of the monoamine transporter of bovine chromaffin granules and other monoamine storage vesicles using 7-azido-8-[125I]iodoketanserin. Biochemistry. 1989;28:2265–2270.PubMedGoogle Scholar
  100. 100.
    Yamada S, Isogai M, Kagawa Y, et al. Brain nicotinic acetylcholine receptors: biochemical characterization by neosurugatoxin. Mol Pharmacol. 1985;28:120–127.PubMedGoogle Scholar
  101. 101.
    Lippiello PM, Fernandes KG. The binding of L-[3H]nicotine to a single class of high affinity sites in rat brain membranes. Mol Pharmacol. 1986;29:448–454.PubMedGoogle Scholar
  102. 102.
    Banerjee S, Abood LG. Nicotine antagonists: phosphoinositide turnover and receptor binding to determine muscarinic properties. Biochem Pharmacol. 1989;38:2933–2935.Google Scholar
  103. 103.
    Broussolle EP, Wong DF, Fanelli RJ, London ED. In vivo specific binding of [3H]L-nicotine in the mouse brain. Life Sci. 1989;44:1123–1132.PubMedGoogle Scholar
  104. 104.
    Damaj MI, Patrick GS, Creasy KR, Martin BR. Pharmacology of lobeline, a nicotinic receptor ligand. J Pharmacol Exp Ther. 1997;282:410–419.PubMedGoogle Scholar
  105. 105.
    Barlow RB, Johnson O. Relations between structure and nicotine-like activity: X-ray crystal structure analysis of (−)-cytisine and (−)-lobeline hydrochloride and a comparison with (−)-nicotine and other nicotine-like compounds. Br J Pharmacol. 1989;98:799–808.PubMedGoogle Scholar
  106. 106.
    Olin BR, Hebel SK, Gremp JL, Hulbertt MK. Smoking deterrents. In: Olin BR, Hebel SK, Gremp JL, Hulbertt MK, eds. Drug Facts and Comparisons. St. Louis, MO: JB Lippincott; 1995:3087–3095Google Scholar
  107. 107.
    Sloan JW, Martin WR, Bostwick M, Hook R, Wala E. The competitive binding characteristics of nicotine ligands and their pharmacology. Pharmacol Biochem Behav. 1988;30:255–267.PubMedGoogle Scholar
  108. 108.
    Brioni JD, O'Neill AB, Kim DJB, Decker MW. Nicotine receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. Eur J Pharmacol. 1993;238:1–8.PubMedGoogle Scholar
  109. 109.
    Decker MW, Majchzark MJ, Arneric SP. Effects of lobeline, a nicotine receptor agonist, on learning and memory. Pharmacol Biochem Behav. 1993;45:571–576.PubMedGoogle Scholar
  110. 110.
    Rasmussen T, Swedberg MDB. Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice. Pharmacol Biochem Behav. 1998;60:567–573.PubMedGoogle Scholar
  111. 111.
    Harrod SB, Dwoskin LP, Green TA, Gehrke BJ, Bardo MT. Lobeline does not serve as a reinforcer in rats. Psychopharmacology (Berl). 2003;165:397–404.Google Scholar
  112. 112.
    Fudala PJ, Iwamoto ET. Further studies on nicotine-induced conditioned place preference in the rat. Pharmacol Biochem Behav. 1986;25:1041–1049.PubMedGoogle Scholar
  113. 113.
    Stolerman IP, Garcha HS, Mirza NR. Dissociation between the locomotor stimulant and depressant effects of nicotinic agonists in rats. Psychopharmacology (Berl). 1995;117:430–437.Google Scholar
  114. 114.
    Dwoskin LP, Crooks PA. A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. Biochem Pharmacol. 2002;63:89–98.PubMedGoogle Scholar
  115. 115.
    Gallardo KA, Leslie FM. Nicotine-stimulated release of [3H]norepinephrine from fetal, rat locus coeruleus cells in culture. J Neurochem. 1998;70:663–670.PubMedGoogle Scholar
  116. 116.
    Miller DK, Crooks PA, Dwoskin LP. Lobeline inhibits nicotine-evoked [3H]dopamine overflow from rat striatal slices and nicotine-evoked 86Rb+ efflux from thalamic synaptosomes. Neuropharmacology. 2000;39:2654–2662.PubMedGoogle Scholar
  117. 117.
    Miller DK, Crooks PA, Zheng G, Grinevich VP, Norrholm S, Dwoskin LP. Lobeline analogues with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters. J Pharmacol Exp Ther. 2004;310:1035–1045.PubMedGoogle Scholar
  118. 118.
    Briggs CA, McKenna DG. Activation and inhibition of the human alpha 7 nicotinic acetylcholine receptor by agonist binding affinity. Mol Pharmacol. 1998;37:1095–1102.Google Scholar
  119. 119.
    Teng L, Crooks PA, Sonsalla PK, Dwoskin LP. Lobeline and nicotine evoke [3H]overflow from rat striatal slices preloaded with [3H]dopamine: differential inhibition of synaptosomal and vesicular [3H]dopamine uptake. J Pharmacol Exp Ther. 1997;280:1432–1444.PubMedGoogle Scholar
  120. 120.
    Teng L, Crooks PA, Dwoskin LP. Lobeline displaces [3H]dihydrotetrabenazine binding and releases [3H]dopamine from rat striatal synaptic vesicles: comparison with d-amphetamine. J Neurochem. 1998;71:258–265.PubMedCrossRefGoogle Scholar
  121. 121.
    Miller DK, Crooks PA, Teng L, et al. Lobeline inhibits the neurochemical and behavioral effects of amphetamine. J. Pharmacol Exp Ther. 2001;296:1023–1034.PubMedGoogle Scholar
  122. 122.
    Miller DK, Harrod SB, Green TA, Wong MY, Bardo MT, Dwoskin LP. Lobeline attenuates the locomotor stimulation induced by repeated nicotine administration in rats. Pharmacol Biochem Behav. 2003;74:279–286.PubMedGoogle Scholar
  123. 123.
    Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT. Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther. 2001;298:172–179.PubMedGoogle Scholar
  124. 124.
    Zheng G, Dwoskin LP, Deaciuc AG, Norrholm SD, Crooks PA. Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter. J Med Chem. 2005;48:5551–5560.PubMedGoogle Scholar
  125. 125.
    Zheng G, Dwoskin LP, Deaciuc AG, Zhu J, Jones MD, Crooks PA. Lobelane analogues, as novel ligands for the vesicular monoamine transporter-2. Bioorg Med Chem. 2005;13:3899–3909.PubMedCrossRefGoogle Scholar
  126. 126.
    Zheng G, Dwoskin LP, Deaciuc AG, Crooks PA. Synthesis and evaluation of a series of tropane analogues as novel vesicular monoamine transporter-2 ligands. Bioorg Med Chem Lett. 2005;15:4463–4466.PubMedGoogle Scholar
  127. 127.
    Perera RP, Wimalasena DS, Wimalasena K. Characterization of a series of 3-amino-2-phenyl-propene derivatives as novel bovine chromaffin vesicular monoamine transporter inhibitors. J Med Chem. 2003;46:2599–2605.PubMedGoogle Scholar
  128. 128.
    Merickel A, Rosandich P, Peter D, Edwards, RH. Identification of residues involved in substrate recognition by a vesicular monoamine transporter. J Biol Chem. 1995;270:25798–25804.PubMedGoogle Scholar
  129. 129.
    Merickel A, Kaback HR, Edwards RH. Charged residues in transmembrane domains II and XI of a vesicular monoamine transporter form a charge pair that promotes high affinity substrate recognition. J Biol Chem. 1997;272:5403–5408.PubMedGoogle Scholar
  130. 130.
    Peter D, Vu T, Edwards RH. Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine. J Biol Chem. 1996;271:2979–2986.PubMedGoogle Scholar
  131. 131.
    Finn JP, III, Edwards RH. Individual residues contribute to multiple differences in ligand recognition between vesicular monoamine transporters 1 and 2. J Biol Chem. 1997;272:16301–16307.PubMedGoogle Scholar
  132. 132.
    Sievert MK, Ruoho AE. Peptide mapping of the [125I]iodoazidok etanserin and [125I]2-N-[(3′-iodo-4′-azidophenyl)propionyl]tetrabenazine binding sites for the synaptic vesicle monoamine transporter. J Biol Chem. 1997;272:26049–26055.PubMedGoogle Scholar
  133. 133.
    Thiriot DS, Ruoho AE. Mutagenesis and derivatization of human vesicle monoamine transporter 2 (VMAT2) cysteines identifies transporter domains involved in tetrabenazine binding and substrate transport. J Biol Chem. 2001;276:27304–27315.PubMedGoogle Scholar
  134. 134.
    Thiriot DS, Sievert MK, Ruoho AE. Identification of human vesicle monoamine transporter (VMAT2) lumenal cysteines that form an intramolecular disulfide bond. Biochemistry. 2002;41: 6346–6353.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • Guangrong Zheng
    • 1
  • Linda P. Dwoskin
    • 1
  • Peter A. Crooks
    • 1
  1. 1.College of PharmacyUniversity of Kentucky, Department of Pharmaceutical SciencesLexington

Personalised recommendations