ArticleThe Journal of pharmacology and experimental therapeutics2011
Novel N-1,2-dihydroxypropyl analogs of lobelane inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release.
Article in The Journal of pharmacology and experimental therapeutics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats.Biochemical pharmacology · 2024Article
- GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine.The Journal of pharmacology and experimental therapeutics · 2019Article
- Varenicline and GZ-793A differentially decrease methamphetamine self-administration under a multiple schedule of reinforcement in rats.Behavioural pharmacology · 2018Article
- GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2.European journal of pharmacology · 2017Article
- Importance of Substrate-Coupled Proton Antiport by the Vesicular Monoamine Transporter in the Actions of Amphetamines inJournal of alcoholism and drug dependence · 2016Article
- Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters · 2016Article
- Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [(3)H]dopamine uptake at the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters · 2016Article
- Preclinical Efficacy of Novel Vesicular Monoamine Transporter 2 Inhibitors as Antagonists of d-Methamphetamine Self-Administration in Rats.Journal of alcoholism and drug dependence · 2015Article
- Quinolyl analogues of norlobelane: novel potent inhibitors of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake at the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters · 2015Article
- The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse.Advances in pharmacology (San Diego, Calif.) · 2014Review
- Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats.Pharmacology, biochemistry, and behavior · 2013Article
- Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo.Journal of neurochemistry · 2013Article
- GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine.Journal of neurochemistry · 2013Article
- New fluorescent substrate enables quantitative and high-throughput examination of vesicular monoamine transporter 2 (VMAT2).ACS chemical biology · 2013Article
- Pyrrolidine analogs of GZ-793A: synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2).Bioorganic & medicinal chemistry letters · 2013Article
- Exploring the effect ofMedChemComm · 2013Article
- The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats.Psychopharmacology · 2012Article
- The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats.Psychopharmacology · 2012Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Lobelane, a chemically defunctionalized saturated analog of lobeline, has increased selectivity for the vesicular monoamine transporter 2 (VMAT2) compared with the parent compound. Lobelane inhibits methamphetamine-evoked dopamine (DA) release and decreases methamphetamine self-administration. Unfortunately, tolerance develops to the ability of lobelane to decrease these behavioral effects of methamphetamine. Lobelane has low water solubility, which is problematic for drug development. The aim of the current study was to determine the pharmacological effect of replacement of the N-methyl moiety with a chiral N-1,2-dihydroxypropyl (N-1,2-diol) moiety, which enhances water solubility, altering the configuration of the N-1,2-diol moiety and incorporating phenyl ring substituents into the analogs. To determine VMAT2 selectivity, structure-activity relationships also were generated for inhibition of DA and serotonin transporters. Analogs with the highest potency for inhibiting DA uptake at VMAT2 and at least 10-fold selectivity were evaluated further for ability to inhibit methamphetamine-evoked DA release from superfused striatal slices. (R)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A), the (R)-4-methoxyphenyl-N-1,2-diol analog, and (R)-3-[2,6-cis-di(1-naphthylethyl)piperidin-1-yl]propane-1,2-diol (GZ-794A), the (R)-1-naphthyl-N-1,2-diol analog, exhibited the highest potency (K(i) ∼30 nM) inhibiting VMAT2, and both analogs inhibited methamphetamine-evoked endogenous DA release (IC(50) = 10.6 and 0.4 μM, respectively). Thus, the pharmacophore for VMAT2 inhibition accommodates the N-1,2-diol moiety, which improves drug-likeness and enhances the potential for the development of these clinical candidates as treatments for methamphetamine abuse.
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