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(CAS: 2141973-99-9 )

Suppliers of GZ-11610

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AMEDCHEM [email protected] +862168061059 CHINA

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Background Information of GZ-11610

GZ-11610 is a vesicular monoamine transporter-2 (VMAT2) inhibitor. VMAT2 is an important pharmacological target for discovery of treatments for methamphetamine use disorder.

Solubility of GZ-11610

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Mechanism and Indications

Signaling Pathways Membrane Transporter/Ion Channel
Target Monoamine Transporter
Research Area Neurological Disease

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase

Chemical Information

M.Wt Formula CAS No. Synonyms
283.41 C19H25NO 2141973-99-9

Structure Information of GZ-11610

Smiles C1C=C(C[[email protected]](NCCCC2C=CC(OC)=CC=2)C)C=CC=1 |&1:4|
InChI InChI=1S/C19H25NO/c1-16(15-18-7-4-3-5-8-18)20-14-6-9-17-10-12-19(21-2)13-11-17/h3-5,7-8,10-13,16,20H,6,9,14-15H2,1-2H3/t16-/m1/s1

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[1].Lee NR, et al. New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders. AAPS J. 2018 Feb 9;20(2):29.
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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