Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake

Derong Ding, Justin R. Nickell, Agripina G. Deaciuc, Narsimha Reddy Penthala, Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a-15c and 22a-22c) potently inhibited [3H]dopamine (DA) uptake into isolated synaptic vesicles (Ki ≤ 66 nM). The cis-4-methoxy analog 22b was the most potent inhibitor (Ki = 24 nM), and was twofold more potent that either lobelane (2a, Ki = 45 nM) or norlobelane (2b, Ki = 43 nM). The trans-methylenedioxy analog, 15c (Ki = 31 nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse.

Original languageEnglish
Pages (from-to)6771-6777
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number21
DOIs
StatePublished - Nov 1 2013

Bibliographical note

Funding Information:
This research was supported by NIH grant U01 DA13519 . The University of Kentucky holds patents on lobeline and the analogs described in the current work. A potential royalty stream to L.P.D. and P.A.C. may occur consistent with University of Kentucky policy.

Keywords

  • Azetidine analogs
  • Lobelane
  • Methamphetamine abuse
  • VMAT2 [H]DA uptake

ASJC Scopus subject areas

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

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