New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• Methamphetamine use disorder lacks effective pharmacotherapies.
• Vesicular monoamine transporter-2 (VMAT2) is a key target for treating stimulant use disorders.
• Previous VMAT2 inhibitors like lobeline and its analogs showed promise but had limitations.

Purpose of the Study:

• To identify and evaluate novel VMAT2 inhibitors for methamphetamine use disorder treatment.
• To assess the selectivity, efficacy, and safety profile of a new compound, GZ-11610.
• To determine if GZ-11610 can mitigate the behavioral effects of methamphetamine.

Main Methods:

• Synthesis and evaluation of a novel N-alkyl(1-methyl-2-phenylethyl)amine scaffold.
• In vitro assessment of VMAT2 inhibition and selectivity against dopamine transporters, serotonin transporters, nicotinic acetylcholine receptors, and hERG channels.
• In vivo testing in methamphetamine-sensitized rats to evaluate GZ-11610's effect on methamphetamine-induced hyperactivity following subcutaneous and oral administration.

Main Results:

• GZ-11610 demonstrated high selectivity for VMAT2 over other targets, including dopamine transporters (290-fold), serotonin transporters (640- to 3500-fold), and nicotinic acetylcholine receptors.
• GZ-11610 exhibited >1000-fold selectivity for VMAT2 over hERG channels, indicating a low potential for cardiotoxicity.
• Oral and subcutaneous administration of GZ-11610 effectively reduced methamphetamine-induced hyperactivity in rats.

Conclusions:

• GZ-11610 is a potent and selective VMAT2 inhibitor with a favorable safety profile.
• The compound shows potential for low abuse liability and reduced cardiotoxicity compared to previous inhibitors.
• GZ-11610 warrants further investigation as a promising therapeutic candidate for methamphetamine use disorder.