title: GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2.
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 (0.3-100µM) inhibited methamphetamine (5µM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1-100µM) inhibited neither nicotine (30µM)-evoked nor electrical field-stimulation-evoked (100Hz/1min) 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.
authors.affiliation: College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.affiliation: College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Kiran B
authors.initials: KB
authors.lastname: Siripurapu
authors.affiliation: College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Horton
authors.affiliation: College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.affiliation: College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.affiliation: College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA. Electronic address: ldwoskin@uky.edu.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D000072237:ERG1 Potassium Channel / Q000378:metabolism; D004558:Electric Stimulation; D057809:HEK293 Cells; D006801:Humans; D008120:Lobeline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013379:Substrate Specificity; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; C573789:N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D008120:Lobeline; D004298:Dopamine
keywords: Dopamine; Drug discovery; Lobelane; Lobeline; Methamphetamine; Vesicular monoamine transporter