title: GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine.
abstract: (R)-3-[2,6-cis-Di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A) inhibits methamphetamine-evoked dopamine release from striatal slices and methamphetamine self-administration in rats. GZ-793A potently and selectively inhibits dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). This study determined GZ-793A's ability to evoke [³H]dopamine release and inhibit methamphetamine-evoked [³H]dopamine release from isolated striatal synaptic vesicles. Results show GZ-793A concentration-dependent [³H]dopamine release; nonlinear regression revealed a two-site model of interaction with VMAT2 (High- and Low-EC₅₀ = 15.5 nM and 29.3 μM, respectively). Tetrabenazine and reserpine completely inhibited GZ-793A-evoked [³H]dopamine release, however, only at the High-affinity site. Low concentrations of GZ-793A that interact with the extravesicular dopamine uptake site and the High-affinity intravesicular DA release site also inhibited methamphetamine-evoked [³H]dopamine release from synaptic vesicles. A rightward shift in the methamphetamine concentration-response was evident with increasing concentrations of GZ-793A, and the Schild regression slope was 0.49 ± 0.08, consistent with surmountable allosteric inhibition. These results support a hypothetical model of GZ-793A interaction at more than one site on the VMAT2 protein, which explains its potent inhibition of dopamine uptake, dopamine release via a High-affinity tetrabenazine- and reserpine-sensitive site, dopamine release via a Low-affinity tetrabenazine- and reserpine-insensitive site, and a low-affinity interaction with the dihydrotetrabenazine binding site on VMAT2. GZ-793A inhibition of the effects of methamphetamine supports its potential as a therapeutic agent for the treatment of methamphetamine abuse.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Horton
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D003627:Data Interpretation, Statistical; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008120:Lobeline / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013747:Tetrabenazine / Q000494:pharmacology; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018765:Dopamine Uptake Inhibitors; C573789:N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D012110:Reserpine; D008120:Lobeline; D004298:Dopamine; D013747:Tetrabenazine
keywords: VMAT2; dopamine release; dopamine uptake; methamphetamine; neuropharmacology; pharmacotherapy