The AAPS Journal

, 20:29 | Cite as

New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders

  • Na-Ra Lee
  • Guangrong Zheng
  • Peter A. Crooks
  • Michael T. Bardo
  • Linda P. Dwoskin
Research Article Theme: Better Drugs for Better Life: Drug Discovery and Development Colloquium 2017
Part of the following topical collections:
  1. Theme: Better Drugs for Better Life: Drug Discovery and Development Colloquium 2017


Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.


dopamine transporter hERG hyperactivity methamphetamine vesicular monoamine transporter-2 


Funding Information

This work was supported by funding from the National Institute of Health grants U01 DA013519 and UL1 TR001998.


  1. 1.
    World Drug Report from the United Nations Office on Drugs and Crime (UNODC) [Internet]. Available from:
  2. 2.
    Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol. 1989;40(1):191–225. Scholar
  3. 3.
    Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U A. 1988;85(14):5274–8. Scholar
  4. 4.
    Gulaboski R, Cordeiro MNDS, Milhazes N, Garrido J, Borges F, Jorge M, et al. Evaluation of the lipophilic properties of opioids, amphetamine-like drugs, and metabolites through electrochemical studies at the interface between two immiscible solutions. Anal Biochem. 2007;361(2):236–43. Scholar
  5. 5.
    Johnson RA, Eshleman AJ, Meyers T, Neve KA, Janowsky A. [3H]substrate- and cell-specific effects of uptake inhibitors on human dopamine and serotonin transporter-mediated efflux. Synap N Y N. 1998;30(1):97–106.<97::AID-SYN12>3.0.CO;2-M.CrossRefGoogle Scholar
  6. 6.
    Mantle TJ, Tipton KF, Garrett NJ. Inhibition of monoamine oxidase by amphetamine and related compounds. Biochem Pharmacol. 1976;25(18):2073–7. Scholar
  7. 7.
    Peter D, Jimenez J, Liu 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(10):7231–7.Google Scholar
  8. 8.
    Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75(6):406–33. Scholar
  9. 9.
    Horton DB, Nickell JR, Zheng G, Crooks PA, Dwoskin LP. GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine. J Neurochem. 2013;127(2):177–86. Scholar
  10. 10.
    Schuldiner S, Steiner-Mordoch S, Yelin R, Wall SC, Rudnick G. Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters. Mol Pharmacol. 1993;44(6):1227–31.Google Scholar
  11. 11.
    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(6):797–808. Scholar
  12. 12.
    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(5 Pt 2):4102–8.Google Scholar
  13. 13.
    Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol. 2007;47(1):681–98. Scholar
  14. 14.
    Volkow ND, Wang G-J, Fowler JS, Tomasi D, Telang F. Addiction: beyond dopamine reward circuitry. Proc Natl Acad Sci U S A. 2011;108(37):15037–42. Scholar
  15. 15.
    Lyness WH, Friedle NM, Moore KE. Destruction of dopaminergic nerve terminals in nucleus accumbens: effect on d-amphetamine self-administration. Pharmacol Biochem Behav. 1979;11(5):553–6. Scholar
  16. 16.
    Dwoskin LP, Crooks PA. A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. Biochem Pharmacol. 2002;63(2):89–98. Scholar
  17. 17.
    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(3):1432–44.Google Scholar
  18. 18.
    Wilhelm CJ, Johnson RA, Lysko PG, Eshleman AJ, Janowsky A. Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system. J Pharmacol Exp Ther. 2004;310(3):1142–51. Scholar
  19. 19.
    Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A. Lobeline effects on tonic and methamphetamine-induced dopamine release. Biochem Pharmacol. 2008;75(6):1411–5. Scholar
  20. 20.
    Nickell JR, Krishnamurthy S, Norrholm S, Deaciuc G, Siripurapu KB, Zheng G, et al. Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2. J Pharmacol Exp Ther. 2010;332(2):612–21. Scholar
  21. 21.
    Miller DK, Crooks PA, Teng L, Witkin JM, Munzar P, Goldberg SR, et al. Lobeline inhibits the neurochemical and behavioral effects of amphetamine. J Pharmacol Exp Ther. 2001;296(3):1023–34.Google Scholar
  22. 22.
    Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT. Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther. 2001;298(1):172–9.Google Scholar
  23. 23.
    Harrod SB, Dwoskin LP, Green TA, Gehrke BJ, Bardo MT. Lobeline does not serve as a reinforcer in rats. Psychopharmacology. 2003;165(4):397–404. Scholar
  24. 24.
    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(1):258–65.CrossRefGoogle Scholar
  25. 25.
    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(17):5551–60. Scholar
  26. 26.
    Nickell JR, Siripurapu KB, Vartak A, Crooks PA, Dwoskin LP, Torres B, et al. The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse. Adv Pharmacol. 2014;69(21):71–106.CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Miller DK, Lever JR, Rodvelt KR, Baskett JA, Will MJ, Kracke GR. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists. Drug Alcohol Depend. 2007;89(2–3):282–91. Scholar
  28. 28.
    Harrod SB, Dwoskin LP, Bardo MT. Lobeline produces conditioned taste avoidance in rats. Pharmacol Biochem Behav. 2004;78(1):1–5. Scholar
  29. 29.
    Glover ED, Rath JM, Sharma E, Glover PN, Laflin M, Tonnesen P, et al. Amulticenter phase 3 trial of lobeline sulfate for smoking cessation. Am J Health Behav. 2010;34(1):101–9.CrossRefGoogle Scholar
  30. 30.
    Miller DK, Harrod SB, Green TA, Wong M-Y, Bardo MT, Dwoskin LP. Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats. Pharmacol Biochem Behav. 2003;74(2):279–86. Scholar
  31. 31.
    Miller DK, Crooks PA, Zheng G, Grinevich VP, Norrholm SD, Dwoskin LP. Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters. J Pharmacol Exp Ther. 2004;310(3):1035–45. Scholar
  32. 32.
    Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT. Lobelane decreases methamphetamine self-administration in rats. Eur J Pharmacol. 2007;571(1):33–8. Scholar
  33. 33.
    Nickell JR, Siripurapu KB, Horton DB, Zheng G, Crooks PA, Dwoskin LP. GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2. Eur J Pharmacol. 2017;795:143–9. Scholar
  34. 34.
    Meyer AC, Neugebauer NM, Zheng G, Crooks PA, Dwoskin LP, Bardo MT. Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo. J Neurochem. 2013;127(2):187–98. Scholar
  35. 35.
    Beckmann JS, Denehy ED, Zheng G, Crooks PA, Dwoskin LP, Bardo MT. The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats. Psychopharmacol Berl. 2012;220(2):395–403. Scholar
  36. 36.
    Alvers KM, Beckmann JS, Zheng G, Crooks PA, Dwoskin LP, Bardo MT. The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats. Psychopharmacol Berl. 2012;224(2):255–62. Scholar
  37. 37.
    Wilmouth CE, Zheng G, Crooks PA, Dwoskin LP, Bardo MT. Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats. Pharmacol Biochem Behav. 2013;112:29–33. Scholar
  38. 38.
    Norrholm SD, Horton DB, Dwoskin LP. The promiscuity of the dopamine transporter: implications for the kinetic analysis of [3H]serotonin uptake in rat hippocampal and striatal synaptosomes. Neuropharmacology. 2007;53(8):982–9. Scholar
  39. 39.
    Horton DB, Siripurapu KB, Norrholm SD, Culver JP, Hojahmat M, Beckmann JS, et al. Meso-Transdiene analogs inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release. J Pharmacol Exp Ther. 2011;336(3):940–51. Scholar
  40. 40.
    Sviripa VM, Zhang W, Balia AG, Tsodikov OV, Nickell JR, Gizard F, et al. 2′,6′-Dihalostyrylanilines, pyridines, and pyrimidines for the inhibition of the catalytic subunit of methionine S-adenosyltransferase-2. J Med Chem. 2014;57(14):6083–91. Scholar
  41. 41.
    Teschemacher AG, Seward EP, Hancox JC, Witchel HJ. Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline. Br J Pharmacol. 1999;128(2):479–85. Scholar
  42. 42.
    Jo SH, Youm JB, Lee CO, Earm YE, Ho WK. Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol. 2000;129(7):1474–80. Scholar
  43. 43.
    Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973;22(23):3099–108.CrossRefGoogle Scholar
  44. 44.
    Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present—a pharmacological and clinical perspective. J Psychopharmacol Oxf Engl. 2013;27(6):479–96. Scholar
  45. 45.
    Stathis M, Scheffel U, Lever SZ, Boja JW, Carroll FI, Kuhar MJ. Rate of binding of various inhibitors at the dopamine transporter in vivo. Psychopharmacology. 1995;119(4):376–84. Scholar
  46. 46.
    Swanson JM, Volkow ND. Serum and brain concentrations of methylphenidate: implications for use and abuse. Neurosci Biobehav Rev. 2003;27(7):615–21. Scholar
  47. 47.
    Volkow ND, Swanson JM. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry. 2003;160(11):1909–18. Scholar
  48. 48.
    German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE. Regulation of the dopamine and vesicular monoamine transporters: pharmacological targets and implications for disease. Pharmacol Rev. 2015;67(4):1005–24. Scholar
  49. 49.
    Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269(5220):92–5. Scholar
  50. 50.
    Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999;97(2):175–87. Scholar
  51. 51.
    Doggrell SA, Hancox JC. Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine. Expert Opin Drug Saf. 2014;13(1):131–8. Scholar
  52. 52.
    Vezina P, Lorrain DS, Arnold GM, Austin JD, Suto N. Sensitization of midbrain dopamine neuron reactivity promotes the pursuit of amphetamine. J Neurosci. 2002;22(11):4654–62.Google Scholar
  53. 53.
    Wang Q, Li D, Bubula N, Campioni MR, McGehee DS, Vezina P. Sensitizing exposure to amphetamine increases AMPA receptor phosphorylation without increasing cell surface expression in the rat nucleus accumbens. Neuropharmacology. 2017;117:328–37. Scholar
  54. 54.
    Kalivas PW, Stewart J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev. 1991;16(3):223–44. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Na-Ra Lee
    • 1
  • Guangrong Zheng
    • 2
  • Peter A. Crooks
    • 2
  • Michael T. Bardo
    • 3
  • Linda P. Dwoskin
    • 1
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA
  2. 2.Department of Pharmaceutical Sciences, College of PharmacyUniversity of Arkansas for Medical SciencesLittle RockUSA
  3. 3.Department of Psychology, College of Arts and SciencesUniversity of KentuckyLexingtonUSA

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