RT Journal Article
SR Electronic
T1 Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 961
OP 967
DO 10.1124/jpet.104.076984
VO 312
IS 3
A1 Hasan Palandoken
A1 Kolbot By
A1 Manu Hegde
A1 William R. Harley
A1 Fredric A. Gorin
A1 Michael H. Nantz
YR 2005
UL http://jpet.aspetjournals.org/content/312/3/961.abstract
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