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 journalArticle

13 Citations (Scopus)

Abstract

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
Volume312
Issue number3
DOIs
StatePublished - Mar 2005

Fingerprint

Amiloride
Prodrugs
Protons
Sodium
Peptides
Neprilysin
Endopeptidases
Reperfusion Injury
Neuroglia
Perfusion
Pharmacology
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Pharmacology

Cite this

Amiloride peptide conjugates : Prodrugs for sodium-proton exchange inhibition. / Palandoken, Hasan; By, Kolbot; Hegde, Manu; Harley, William R.; Gorin, Fredric A; Nantz, Michael H.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 312, No. 3, 03.2005, p. 961-967.

Research output: Contribution to journalArticle

Palandoken, Hasan ; By, Kolbot ; Hegde, Manu ; Harley, William R. ; Gorin, Fredric A ; Nantz, Michael H. / Amiloride peptide conjugates : Prodrugs for sodium-proton exchange inhibition. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 312, No. 3. pp. 961-967.
@article{cb1fbab1821f4a09999fd1a666fad728,
title = "Amiloride peptide conjugates: Prodrugs for sodium-proton exchange inhibition",
abstract = "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.",
author = "Hasan Palandoken and Kolbot By and Manu Hegde and Harley, {William R.} and Gorin, {Fredric A} and Nantz, {Michael H.}",
year = "2005",
month = "3",
doi = "10.1124/jpet.104.076984",
language = "English (US)",
volume = "312",
pages = "961--967",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Amiloride peptide conjugates

T2 - Prodrugs for sodium-proton exchange inhibition

AU - Palandoken, Hasan

AU - By, Kolbot

AU - Hegde, Manu

AU - Harley, William R.

AU - Gorin, Fredric A

AU - Nantz, Michael H.

PY - 2005/3

Y1 - 2005/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=14344251490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14344251490&partnerID=8YFLogxK

U2 - 10.1124/jpet.104.076984

DO - 10.1124/jpet.104.076984

M3 - Article

VL - 312

SP - 961

EP - 967

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -