GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2

Justin R. Nickell, Kiran B. Siripurapu, David B. Horton, Guangrong Zheng, Peter A. Crooks, Linda P. Dwoskin

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Lobeline and lobelane inhibit the behavioral and neurochemical effects of methamphetamine via an interaction with the vesicular monoamine transporter-2 (VMAT2). However, lobeline has high affinity for nicotinic receptors, and tolerance develops to the behavioral effects of lobelane. A water-soluble analog of lobelane, R-N-(1,2–dihydroxypropyl)−2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), also interacts selectively with VMAT2 to inhibit the effects of methamphetamine, but does not produce behavioral tolerance. The current study further evaluated the mechanism underlying the GZ-793A-mediated inhibition of the neurochemical effects of methamphetamine. In contrast to lobeline, GZ-793A does not interact with the agonist recognition site on α4β2*and α7*nicotinic receptors. GZ-793A (0.3–100 µM) inhibited methamphetamine (5 µM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1–100 µM) inhibited neither nicotine (30 µM)-evoked nor electrical field-stimulation-evoked (100 Hz/1 min) fractional dopamine release. Unfortunately, GZ-793A inhibited [3H]dofetilide binding to human-ether-a-go-go related gene channels expressed on human embryonic kidney cells, and further, prolonged action potentials in rabbit cardiac Purkinje fibers, suggesting the potential for GZ-793A to induce ventricular arrhythmias. Thus, GZ-793A selectively inhibits the neurochemical effects of methamphetamine and lacks nicotinic receptor interactions; however, development as a pharmacotherapy for methamphetamine use disorders will not be pursued due to its potential cardiac liabilities.

Original languageEnglish
Pages (from-to)143-149
Number of pages7
JournalEuropean Journal of Pharmacology
Volume795
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
This research was supported by NIH Grants U01 DA13519, UL1TR000117, P20 GM109005, and an Arkansas Research Alliance (ARA) Scholar award.

Publisher Copyright:
© 2016

Keywords

  • Dopamine
  • Drug discovery
  • Lobelane
  • Lobeline
  • Methamphetamine
  • Vesicular monoamine transporter

ASJC Scopus subject areas

  • Pharmacology

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