TY - JOUR T1 - GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.258699 SP - jpet.119.258699 AU - Na-Ra Lee AU - Guangrong Zheng AU - Markos Leggas AU - Venumadhav Janganati AU - Justin R. Nickell AU - Peter A. Crooks AU - Michael T. Bardo AU - Linda Dwoskin Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/08/14/jpet.119.258699.abstract N2 - Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program identified R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor that specifically decreased methamphetamine's behavioral effects. However, GZ-793A inhibited human hERG channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of the piperidine ring in GZ-793A with a phenylalkyl group to provide 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 DA release were determined. GZ-11608 doses that decreased methamphetamine-sensitized activity were used to evaluate 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 (Ki=25 nM) and selectivity (92-1180-fold) for VMAT2 over nicotinic receptors, the dopamine transporter and hERG, suggesting low side-effect potential. GZ-11608 (EC50=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=0.9±0.13). GZ-11608 decreased methamphetamine-sensitized activity, without altering striatal dopamine content or exacerbating methamphetamine-induced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 decreased methamphetamine self-administration, which was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue- and methamphetamine-induced reinstatement, suggesting its 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 (VMAT2) inhibitor that decreases methamphetamine-induced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetamine sensitized 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 lead in our search for a therapeutic to treat methamphetamine use disorder. ER -