Amiloride peptide conjugates: Prodrugs for sodium-proton exchange inhibition

Hasan Palandoken, Kolbot By, Manu Hegde, William R. Harley, Fredric A Gorin, Michael H. Nantz

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Inhibition of the sodium-proton exchanger (NHE) plays an important role in reducing tissue damage during ischemic reperfusion injury; however, pharmacological inhibitors of NHE have restricted access to acutely ischemic tissues because of severely compromised tissue perfusion. We describe the syntheses, characterization, and NHE inhibitory activities of a novel class of amiloride derivatives where peptides are conjugated to the amiloride C(5) amino group. These new peptide-C(5)-amiloride conjugates are inactive; however, peptide residues were chosen such that selective cleavage by neutral endopeptidase 24.11 (enkephalinase) liberates an amino acid-C(5)-amiloride conjugate that inhibits NHE in a glial cell line. These results confirm the feasibility of using peptide-amiloride conjugates as NHE inhibitor prodrugs. We envision the design of analogous peptide-amiloride prodrugs that can be administered prior to ischemic events and subsequently activated by endopeptidases selectively expressed by ischemic tissues.

Original languageEnglish (US)
Pages (from-to)961-967
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Mar 2005

ASJC Scopus subject areas

  • Pharmacology


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