Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2

Justin R. Nickell, John P. Culver, Venumadhav Janganati, Guangrong Zheng, Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

A small library of 1,4-diphenethylpiperazine analogs was synthesized and evaluated for inhibition of [3H]dihydrotetrabenazine binding and [3H]dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). Results from these studies identified three novel molecules, 6b, 6e and 9a (Ki = 35 nM, 48 nM and 37 nM, respectively) that exhibit similar potency for inhibition of VMAT2 function compared with lobelane (Ki = 45 nM), and importantly, have enhanced water-solubility when compared to the previously reported 1,4-diphenethylpiperidine analogs. These 1,4-diphenethylpiperazine analogs constitute promising new leads in the discovery of potential pharmacotherapeutics for treatment of methamphetamine use disorders.

Original languageEnglish
Pages (from-to)4441-4445
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number18
DOIs
StatePublished - Sep 15 2016

Bibliographical note

Funding Information:
This research was supported by NIH (United States) grants DA 13519 , TR 00117 , DA 016176 , and GM 109005 , and by an Arkansas Research Alliance (United States) Scholar award. Methods for the [ 3 H]DTBZ and [ 3 H]dofetilide binding assays and [ 3 H]DA and [ 3 H]5-HT uptake assays, and full characterization data for all synthetic products, can be found in the Supporting Information.

Publisher Copyright:
© 2016 Elsevier Ltd

Keywords

  • Dopamine uptake
  • Lobelane
  • Phenethyl bromides
  • Piperazine analogs
  • VMAT2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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