The vesicular monoamine transporter-2: An important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse

Justin R. Nickell, Kiran B. Siripurapu, Ashish Vartak, Peter A. Crooks, Linda P. Dwoskin

Research output: Chapter in Book/Report/Conference proceedingChapter

21 Scopus citations

Abstract

Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic.

Original languageEnglish (US)
Title of host publicationAdvances in Pharmacology
PublisherAcademic Press Inc.
Pages71-106
Number of pages36
DOIs
StatePublished - 2014

Publication series

NameAdvances in Pharmacology
Volume69
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925

Keywords

  • AV-2-192
  • GZ-793A
  • Lobelane
  • Lobeline
  • Methamphetamine
  • VMAT2

Fingerprint Dive into the research topics of 'The vesicular monoamine transporter-2: An important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse'. Together they form a unique fingerprint.

  • Cite this

    Nickell, J. R., Siripurapu, K. B., Vartak, A., Crooks, P. A., & Dwoskin, L. P. (2014). The vesicular monoamine transporter-2: An important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse. In Advances in Pharmacology (pp. 71-106). (Advances in Pharmacology; Vol. 69). Academic Press Inc.. https://doi.org/10.1016/B978-0-12-420118-7.00002-0