meso-Transdiene Analogs Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

Horton, David B.; Siripurapu, Kiran B.; Norrholm, Seth D.; Culver, John P.; Hojahmat, Marhaba; Beckmann, Joshua S.; Harrod, Steven B.; Deaciuc, Agripina G.; Bardo, Michael T.; Crooks, Peter A.; Dwoskin, Linda P.

doi:10.1124/jpet.110.175117

Cited by 15 publications

(20 citation statements)

References 32 publications

(39 reference statements)

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“…Considerable attention has been given to positive rewarding effects associated with MA addiction (Beckmann et al, 2010;Horton et al, 2011;Kamens et al, 2005;Mahler et al, 2013;Meyer et al, 2011;Mizoguchi et al, 2004;Shabani et al, 2011Shabani et al, , 2012aWheeler et al, 2009), whereas aversive effects that could limit intake have been given less consideration (Harrod et al, 2010;Pringle et al, 2008;Shabani et al, 2011Shabani et al, , 2012bWheeler et al, 2009). Greater Figure 3 (a) Methamphetamine (MA) consumption differs by Taar1 genotype.…”

Section: Discussionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

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Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA-induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use.

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Section: Discussionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

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“…Samples were filtered rapidly through Whatman GF/B filters using the cell harvester and washed three times with assay buffer containing 2 mM MgSO 4 in the absence of ATP. Radioactivity retained by the filters was determined as described under Rat coronal striatal slices of 0.5-mm thickness were prepared and incubated in Krebs' buffer, containing 118 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl 2 , 1.0 mM NaH 2 PO 4 , 1.3 mM CaCl 2 , 11.1 mM ␣-D-glucose, 25 mM NaHCO 3 , 0.11 mM L-ascorbic acid, and 0.004 mM EDTA, pH 7.4, saturated with 95% O 2 /5% CO 2 at 34°C in a metabolic shaker for 60 min (Horton et al, 2011). Each slice was transferred to a glass superfusion chamber and superfused with Krebs' buffer at 1 ml/min for 60 min before sample collection.…”

Section: Animalsmentioning

confidence: 99%

“…Analog-induced inhibition of [ 3 H]DTBZ binding, a high-affinity ligand for VMAT2, was determined using modifications of a previously published method (Horton et al, 2011). Rat whole brain (excluding cerebellum) was homogenized in 20 ml of ice-cold 0.32 M sucrose solution with 10 up-and-down strokes of a Teflon pestle homogenizer (clearance ϳ0.008 inch).…”

Section: Animalsmentioning

confidence: 99%

“…, and (S)-3-[2,6-cis-di (3,4-methylenedioxyphenethyl) ]5-HT uptake into rat striatal and hippocampal synaptosomes, respectively, was determined using modifications of a previously described method (Horton et al, 2011). Brain regions were homogenized in 20 ml of ice-cold 0.32 M sucrose solution containing 5 mM NaHCO 3 , pH 7.4, with 16 up-and-down strokes of a Teflon pestle homogenizer (clearance ϳ0.005 inch).…”

Section: Animalsmentioning

confidence: 99%

“…Taking into account VMAT2 as a component of the mechanism of action of methamphetamine, our research focus has been the discovery of novel therapeutic agents that target VMAT2. Structure-activity relationships (SARs) have been generated to elucidate novel pharmacophores that modify VMAT2 function with the aim of developing effective treatments for methamphetamine abuse (Zheng et al, 2005a,b;Crooks et al, 2010;Nickell et al, 2010Nickell et al, , 2011Horton et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

Horton¹,

Siripurapu²,

Zheng³

et al. 2011

J Pharmacol Exp Ther

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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 ϳ30 nM) inhibiting VMAT2, and both analogs inhibited methamphetamine-evoked endogenous DA release (IC 50 ϭ 10.6 and 0.4 M, 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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HPLC‐ESI‐MS/MS of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia inflata L

Kursinszki

Szöke

2015

J. Mass Spectrom.

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There is a renewed interest in lobelia alkaloids because of their activity on the central nervous system. Lobeline, the most active of them, a nicotinic receptor ligand and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for metamphetamine abuse. In the present work, high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry in positive ion mode was used for investigating the alkaloid profile in Lobelia inflata L. Chromatographic separations were achieved on a Gemini C6-phenyl reversed-phase column providing good peak shape and improved selectivity. Being mostly 2,6-disubstituted piperidines, lobelia alkaloids presented abundant [M + H](+) ions with typical fragmentation. Identification was possible from a few specific ions, especially those resulting from excision of one of the substituents. Based on fragmentation pattern of lobeline as reference compound, 52 alkaloids were identified in the aqueous methanolic extract of L. inflata in contrast to the previously known some 20. Structural variability of these alkaloids identified arises basically from their substituents which can be phenyl-2-ketoethyl- or phenyl-2-hydroxyethyl units as well as their methyl-, ethyl- or propyl- homologues attached in different combinations. Several propyl homologue lobelia alkaloids and five hydroxypiperidine derivatives were found in the plant at the first time. In addition to 8-O-esters of 2-monosubstituted piperidine alkaloids previously reported by us in L. inflata, a 3-hydroxy-3-phenylpropanoic acid ester of hydroxyallosedamine ring-substituted was also identified as a new natural product. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry can be successfully applied to Lobeliacae plant samples in the routine screening for new and known bioactive constituents, quality control of the crude drug, lobelia herba, alkaloid production studies, breeding and chemotaxonomy.

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meso-Transdiene Analogs Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

Cited by 15 publications

References 32 publications

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

HPLC‐ESI‐MS/MS of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia inflata L

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