<scp>GZ</scp>‐793A, a lobelane analog, interacts with the vesicular monoamine transporter‐2 to inhibit the effect of methamphetamine

Horton, David B.; Nickell, Justin R.; Zheng, Guangrong; Crooks, Peter A.; Dwoskin, Linda P.

doi:10.1111/jnc.12371

Cited by 13 publications

(17 citation statements)

References 29 publications

(103 reference statements)

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“…3B). Kinetic parameters for methamphetamineevoked [ 3 H]DA release from striatal synaptic vesicles were consistent with previously published values (Horton et al, 2013). Concentration-response data for methamphetamine in the presence of varying GZ-11608 concentrations (10, 500 nM, or 10 mM) each fit a one-site model (nonlinear regression, R 2 5 0.94, 0.95, 0.90, respectively, multiple P values , 0.0001; Fig.…”

Section: Gz-11608 Potently and Selectively Inhibits Vmat2 Function Resupporting

confidence: 89%

“…Interaction of methamphetamine with the dopamine system underlies its abuse liability (Koob and Volkow, 2016). Methamphetamine increases cytosolic dopamine concentration by releasing vesicular dopamine (EC 50 5 9-15 mM, E max 5 90%) and inhibiting vesicular uptake (K i 5 2.5 mM) (Nickell et al, 2010;Horton et al, 2013;current study). At VMAT2, methamphetamine inhibits uptake approx.…”

Section: Discussionmentioning

confidence: 99%

“…Methamphetamine-Evoked [ 3 H]DA Release. To further evaluate GZ-11608 efficacy as an inhibitor of the pharmacological effects of methamphetamine, the concentration-dependent effect of GZ-11608 to inhibit methamphetamine-evoked dopamine release from isolated striatal synaptic vesicles was determined using previously described methods (Teng et al, 1997;Horton et al, 2013). Also, the underlying mechanism of GZ-11608 inhibition was determined.…”

Section: Methodsmentioning

confidence: 99%

“…1), which contains an N-1,2-dihydroxypropyl in place of the N-methyl group in lobelane (Horton et al, 2011b). GZ-793A exhibited high affinity (K i 5 29 nM) for VMAT2, and inhibited methamphetamine-evoked dopamine release from striatal slices and synaptic vesicular preparations and from nucleus accumbens in in vivo microdialysis studies (Horton et al, 2011b(Horton et al, , 2013Meyer et al, 2013;Nickell et al, 2017). GZ-793A decreased methamphetamine selfadministration and reinstatement of methamphetamineseeking behavior (Alvers et al, 2012;Beckmann et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine

Lee

Zheng

Leggas

et al. 2019

J Pharmacol Exp Ther

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Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program had found that R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine's behavioral effects. However, GZ-793A inhibited human-ether-ago go related gene (hERG) channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of GZ-793A's piperidine ring with a phenylalkyl group to yield S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11608) diminished hERG interaction while retaining pharmacological efficacy. VMAT2 inhibition, target selectivity, and mechanism of GZ-11608-induced inhibition of methamphetamineevoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetaminesensitized activity to evaluate the potential exacerbation of methamphetamine-induced dopaminergic neurotoxicity. GZ-11608-induced decreases in methamphetamine reinforcement and abuse liability were determined using self-administration, reinstatement, and substitution assays. Results show that GZ-11608 exhibited high affinity (K i 5 25 nM) and selectivity (92-1180-fold) for VMAT2 over nicotinic receptors, dopamine transporter, and hERG, suggesting low side-effects. GZ-11608 (EC 50 5 620 nM) released vesicular dopamine 25-fold less potently than it inhibited VMAT2 dopamine uptake. GZ-11608 competitively inhibited methamphetamine-evoked vesicular dopamine release (Schild regression slope 5 0.9 6 0.13). GZ-11608 decreased methamphetamine sensitization without altering striatal dopamine content or exacerbating methamphetamineinduced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 exhibited linear pharmacokinetics and rapid brain penetration. GZ-11608 decreased methamphetamine self-administration, and this effect was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue-and methamphetamine-induced reinstatement, suggesting potential to prevent relapse. GZ-11608 neither served as a reinforcer nor substituted for methamphetamine, suggesting low abuse liability. Thus, GZ-11608, a potent and selective VMAT2 inhibitor, shows promise as a therapeutic for methamphetamine use disorder. SIGNIFICANCE STATEMENT GZ-11608 is a potent and selective vesicular monoamine transporter-2 inhibitor that decreases methamphetamineinduced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetaminesensitized locomotor activity, methamphetamine self-administration, and reinstatement of methamphetamine-seeking behavior, without exhibiting abuse liability. Tolerance does not develop to the efficacy of GZ-11608 to decrease the behavioral effects of methamphetamine. In conclusion, GZ-11608 is an outstanding le...

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Section: Gz-11608 Potently and Selectively Inhibits Vmat2 Function Resupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine

Lee

Zheng

Leggas

et al. 2019

J Pharmacol Exp Ther

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“…Importantly, GZ-793A inhibited METH-evoked DA release from superfused striatal slices (Horton, Siripurapu, Zheng, et al, 2011), and GZ-793A reduced the duration of the METH-induced increase in extracellular DA in nucleus accumbens in microdialysis studies (Meyer et al, 2013). Taking a more molecular approach, GZ-793A was found recently to inhibit METH-evoked DA release from isolated striatal synaptic vesicles via a surmountable allosteric inhibition and to interact with VMAT2 at several distinct sites on the protein, both extravesicular and intravesicular (Horton, Nickell, Zheng, Crooks, & Dwoskin, 2013). These results from the neurochemical assays support VMAT2 as an important pharmacological target and GZ-793A as a lead compound for reducing the neurochemical effects of METH.…”

Section: Discussionmentioning

confidence: 99%

The Vesicular Monoamine Transporter-2

Nickell

Siripurapu

Vartak

et al. 2014

Advances in Pharmacology

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Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic.

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