Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity

Alan P. Kozikowski, Daniele Simoni, Marinella Roberti, Riccardo Rondanin, Shaomeng Wang, Pingfeng Du, Kenneth M. Johnson

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

In order to further explore the importance of cocaine's bridge nitrogen atom in binding to the dopamine transporter (DAT), we have synthesized the previously known racemic 8-oxa-norcocaines 3-6 in which the nitrogen atom has been replaced by oxygen. Additionally, to avoid incorrect interpretations of biological data that may stem from the use of racemic materials, several of these analogues were synthesized and tested in non-racemic form. (-)-8-Oxa- norcocaine (3) was found to bind to the cocaine recognition site and to inhibit the dopamine transporter with potencies only about 8-fold and 4- fold, respectively, less than those of norcocaine (2). (-)-8-Oxa- pseudonorcocaine (4) as well as (+)-8-oxa-norcocaine (3) were found to be comparable in activity to (-)-oxa-norcocaine. These pharmacological findings support our earlier suggestion that cocaine is likely to bind in its neutral form to the DAT.

Original languageEnglish (US)
Pages (from-to)1831-1836
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume9
Issue number13
DOIs
StatePublished - Jul 5 1999

ASJC Scopus subject areas

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

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    Kozikowski, A. P., Simoni, D., Roberti, M., Rondanin, R., Wang, S., Du, P., & Johnson, K. M. (1999). Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity. Bioorganic and Medicinal Chemistry Letters, 9(13), 1831-1836. https://doi.org/10.1016/S0960-894X(99)00273-5