Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

Nickell, Justin R.; Krishnamurthy, Sairam; Norrholm, Seth D.; Deaciuc, Gabriela; Siripurapu, Kiran B.; Zheng, Guangrong; Crooks, Peter A.; Dwoskin, Linda P.

doi:10.1124/jpet.109.160275

Cited by 49 publications

(81 citation statements)

References 28 publications

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“…2. K i values for GBR 12909, cocaine, lobeline, and lobelane (Table 1) are consistent with previously reported findings (Reith et al, 1994;Han and Gu, 2006;Nickell et al, 2010). Replacement of the N-methyl in lobelane with a N-1,2-diol moiety generally afforded analogs that were 1-to 10-fold less potent (K i ϭ 1.43-9.5 M) at DAT compared with lobelane.…”

Section: N-12-diol Analogs Inhibit [supporting

confidence: 81%

“…Through an interaction with VMAT2, lobeline inhibits the neurochemical and behavioral effects of methamphetamine (Teng et al, 1997(Teng et al, , 1998Harrod et al, 2001;Miller et al, 2001;Dwoskin and Crooks, 2002;Nickell et al, 2010). Lobelane, a lobeline analog with greater selectivity for VMAT2, decreased both methamphetamineevoked DA release (IC 50 ϭ 0.65 M; I max ϭ 73.2%; same experimental conditions as the current work) and methamphetamine self-administration (Zheng et al, 2005a;Neugebauer et al, 2007;Beckmann et al, 2010;Nickell et al, 2010Nickell et al, , 2011. Unfortunately, further development of lobelane as an effective pharmacotherapy was hindered by unacceptable drug-likeness properties.…”

Section: Discussionmentioning

confidence: 99%

“…1), the principal alkaloid in Lobelia inflata, inhibits the neurochemical and behavioral effects of methamphetamine through its interaction with VMAT2 (Teng et al, 1997(Teng et al, , 1998Harrod et al, 2001;Miller et al, 2001;Dwoskin and Crooks, 2002;Nickell et al, 2010 Teng et al, 1997Teng et al, , 1998, and methamphetamine-evoked DA release (IC 50 ϭ 0.42 M), supporting the tenet that VMAT2 is a viable therapeutic target for the development of treatments for methamphetamine abuse. In further support of this hypothesis, lobeline decreases methamphetamine selfadministration in rats (Harrod et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…1), a chemically defunctionalized, saturated analog of lobeline, competitively inhibited DA uptake at VMAT2 and exhibited increased affinity and selectivity for VMAT2 compared with lobeline (Miller et al, 2001;. Lobelane inhibited methamphetamine-evoked DA release and decreased methamphetamine self-administration; however, tolerance developed to the latter behavior effects (Neugebauer et al, 2007;Nickell et al, 2010). Unfortunately, lobelane exhibits decreased water solubility and diminished drug-likeness properties caused by its decreased polarity resulting from removal of the keto and hydroxyl functionalities of lobeline.…”

Section: Introductionmentioning

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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Section: N-12-diol Analogs Inhibit [supporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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Plant and Marine Sources

Amedei

Niccolai

2014

Natural Products Analysis

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Interactions of Cannabis and Amphetamine-Type Stimulants

Tambaro

Bortolato

2015

Cannabinoid Modulation of Emotion, Memory, and Motivation

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Amphetamine-type stimulants (ATSs) are a large family of substances of abuse, characterized by well-known mood-and performance-enhancing properties. This class encompasses several high-potency stimulants and entactogens, such as the precursor compound d-amphetamine (AMPH), its synthetic N-methylated derivatives methamphetamine (METH) and 3, 4-methylenedioxy-N-methylamphetamine (MDMA, or "ecstasy"), as well as novel designer drugs, based on substituted forms of the natural alkaloid cathinone. ATSs (and in particular METH) are among the most commonly abused substances worldwide, second only to Cannabis sativa; indeed, the rate of concurrent consumption of METH and cannabis has been increasing over the last decade, particularly among adolescents. Anecdotal evidence suggests that marijuana may offset some unpleasant subjective effects of ATSs, such as anxiety and paranoia. Both drugs have been shown to increase schizophrenia vulnerability in young vulnerable individuals, raising the possibility that their concurrent intake may have synergistic effects with respect to the development of psychotic manifestations. In addition, the combination of these two substances may affect their subjective effects and exacerbate their abuse liability. Although current evidence on the neurobiological interactions of cannabis and ATSs remains mostly elusive, initial studies in animal models suggest that the cannabinoid system may play a relevant role in the motivational and addictive properties of ATSs; furthermore, cannabinoids may modify the behavioral effects and even attenuate some untoward long-term consequences of ATSs. In this chapter we review the available evidence on these potential interactions and outline some key mechanisms that may account for the mutual modulatory influence of these substances.

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Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

Cited by 49 publications

References 28 publications

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

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

Plant and Marine Sources

Interactions of Cannabis and Amphetamine-Type Stimulants

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