Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate

William Nguyen, Brittany L. Howard, David P. Jenkins, Heike Wulff, Philip E. Thompson, David T. Manallack

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC50 values.

Original languageEnglish (US)
Pages (from-to)7106-7109
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number23
StatePublished - Dec 1 2012


  • Autoimmune disease
  • Electrophysiology
  • Ion channel blockers
  • Kv1.3
  • Medicinal chemistry

ASJC Scopus subject areas

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


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