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

Authors

Na-Ra Lee, University of KentuckyFollow
Guangrong Zheng, University of Florida
Markos Leggas, University of KentuckyFollow
Venumadhav Janganati, University of Arkansas for Medical Sciences
Justin R. Nickell, University of KentuckyFollow
Peter A. Crooks, University of Arkansas for Medical SciencesFollow
Michael T. Bardo, University of KentuckyFollow
Linda P. Dwoskin, University of KentuckyFollow

Abstract

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-methoxy-phenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine’s behavioral effects. However, GZ-793A inhibited human-ether-a-go-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 methamphetamine-evoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetamine-sensitized 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 methamphetamine-induced 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.

Document Type

Article

Publication Date

2019

Notes/Citation Information

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics

Digital Object Identifier (DOI)

https://doi.org/10.1124/jpet.119.258699

Funding Information

This work was supported with funding from the National Institutes of Health Grants U01 DA013519, U01 DA043908, and UL1 TR001998.

Repository Citation

Lee, Na-Ra; Zheng, Guangrong; Leggas, Markos; Janganati, Venumadhav; Nickell, Justin R.; Crooks, Peter A.; Bardo, Michael T.; and Dwoskin, Linda P., "GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine" (2019). Psychology Faculty Publications. 237.
https://uknowledge.uky.edu/psychology_facpub/237