1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Shawn Maddaford, Paul Renton, Joanne Speed, Subhash C. Annedi, Jailall Ramnauth, Suman Rakhit, John Andrews, Gabriela Mladenova, Lisa Majuta, Frank Porreca

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain.

Original languageEnglish (US)
Pages (from-to)5234-5238
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2011

Keywords

  • 1,6-Disubstitued indole derivatives
  • Nitric oxide
  • Nitric oxide synthase
  • Nitric oxide synthase inhibitors
  • Selective neuronal nitric oxide synthase inhibitors

ASJC Scopus subject areas

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

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  • Cite this

    Maddaford, S., Renton, P., Speed, J., Annedi, S. C., Ramnauth, J., Rakhit, S., Andrews, J., Mladenova, G., Majuta, L., & Porreca, F. (2011). 1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. Bioorganic and Medicinal Chemistry Letters, 21(18), 5234-5238. https://doi.org/10.1016/j.bmcl.2011.07.042