PT  - JOURNAL ARTICLE
AU  - Hasan Palandoken
AU  - Kolbot By
AU  - Manu Hegde
AU  - William R. Harley
AU  - Fredric A. Gorin
AU  - Michael H. Nantz
TI  - Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition
AID  - 10.1124/jpet.104.076984
DP  - 2005 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 961--967
VI  - 312
IP  - 3
4099  - http://jpet.aspetjournals.org/content/312/3/961.short
4100  - http://jpet.aspetjournals.org/content/312/3/961.full
SO  - J Pharmacol Exp Ther2005 Mar 01; 312
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. The American Society for Pharmacology and Experimental Therapeutics