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

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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(DAT), we have synthesized the previously known racemic 8-oxa-norcocaines 3-6 in which the nitrogen atom has been replaced by oxygen.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

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Dopamine Plasma Membrane Transport Proteins
Cocaine
Nitrogen
Atoms
Pharmacology
Oxygen
norcocaine
8-oxanorcocaine

ASJC Scopus subject areas

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

Cite this

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

Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity. / Kozikowski, Alan P.; Simoni, Daniele; Roberti, Marinella; Rondanin, Riccardo; Wang, Shaomeng; Du, Pingfeng; Johnson, Kenneth M.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 9, No. 13, 05.07.1999, p. 1831-1836.

Research output: Contribution to journalArticle

Kozikowski, AP, Simoni, D, Roberti, M, Rondanin, R, Wang, S, Du, P & Johnson, KM 1999, 'Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity', Bioorganic and Medicinal Chemistry Letters, vol. 9, no. 13, pp. 1831-1836. https://doi.org/10.1016/S0960-894X(99)00273-5
Kozikowski, Alan P. ; Simoni, Daniele ; Roberti, Marinella ; Rondanin, Riccardo ; Wang, Shaomeng ; Du, Pingfeng ; Johnson, Kenneth M. / Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity. In: Bioorganic and Medicinal Chemistry Letters. 1999 ; Vol. 9, No. 13. pp. 1831-1836.
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