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New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders

  • Research Article
  • Theme: Better Drugs for Better Life: Drug Discovery and Development Colloquium 2017
  • Published:
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Abstract

Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3–30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.

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Funding

This work was supported by funding from the National Institute of Health grants U01 DA013519 and UL1 TR001998.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 465 TODD Building, 789 South Limestone, Lexington, Kentucky, 40536-0596, USA

    Na-Ra Lee & Linda P. Dwoskin

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    Guangrong Zheng & Peter A. Crooks

  3. Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, Kentucky, USA

    Michael T. Bardo

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  1. Na-Ra Lee
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  2. Guangrong Zheng
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  3. Peter A. Crooks
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  4. Michael T. Bardo
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  5. Linda P. Dwoskin
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Correspondence to Linda P. Dwoskin.

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Guest Editors: Shraddha Thakkar and Cesar M. Compadre

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Lee, NR., Zheng, G., Crooks, P.A. et al. New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders. AAPS J 20, 29 (2018). https://doi.org/10.1208/s12248-018-0192-y

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