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 journalArticle

6 Citations (Scopus)

Abstract

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
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2012

Fingerprint

Diphenoxylate
Structure-Activity Relationship
Functional groups
Kv1.3 Potassium Channel
Nitriles
Opioid Analgesics
Autoimmune Diseases
Inhibitory Concentration 50
Therapeutics

Keywords

  • 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

Cite this

Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate. / Nguyen, William; Howard, Brittany L.; Jenkins, David P.; Wulff, Heike; Thompson, Philip E.; Manallack, David T.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 23, 01.12.2012, p. 7106-7109.

Research output: Contribution to journalArticle

Nguyen, William ; Howard, Brittany L. ; Jenkins, David P. ; Wulff, Heike ; Thompson, Philip E. ; Manallack, David T. / Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 23. pp. 7106-7109.
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