Quinolyl analogues of norlobelane: Novel potent inhibitors of [3H]dihydrotetrabenazine binding and [3H]dopamine uptake at the vesicular monoamine transporter-2

Derong Ding, Justin R. Nickell, Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

We have previously shown that quinolyl moieties are attractive structural replacements for the phenyl groups in lobelane. These quinolyl analogues had improved water-solubility over lobelane and retained the potent vesicular monoamine transporter-2 (VMAT-2) inhibitory properties of the parent compound, with quinlobelane (4) exhibiting potent inhibition of uptake at VMAT-2 (Ki = 51 nM). However, the VMAT-2 inhibitory properties of quinolyl analogues of norlobelane, which is equipotent with lobeline as an inhibitor of [3H]dopamine (DA) uptake at VMAT-2, have not been reported. In the current communication, we describe the synthesis of some novel des-methyl quinolyl analogues of lobelane that exhibit greater affinity (Ki = 178-647 nM) for the dihydrotetrabenazine binding site located on VMAT-2 compared with lobelane (Ki = 970 nM), norlobelane (Ki = 2310 nM) and quinlobelane (Ki = 2640 nM). The most potent compounds, 14 and 15, also exhibited inhibition of [3H]DA uptake at VMAT-2 (Ki = 42 nM) which was comparable to both lobelane (Ki = 45 nM) and norlobelane (Ki = 43 nM). Results reveal that binding affinity at VMAT-2 serves as an accurate predictor of inhibition of the function of VMAT-2 for the majority of these analogues. These novel analogues are under consideration for further development as treatments for methamphetamine abuse.

Original languageEnglish
Pages (from-to)2613-2616
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number13
DOIs
StatePublished - May 30 2015

Bibliographical note

Funding Information:
The authors gratefully acknowledge the technical assistance of Ms. Agripina G. Deaciuc and funding support from NIH grant U01 DA13519.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

  • Methamphetamine abuse
  • Quinolyl analogues of norlobelane
  • VMAT-2
  • Vesicular [H]dopamine uptake

ASJC Scopus subject areas

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

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