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.
authors.affiliation: Department of Neurology, University of California School of Medicine, Davis, CA 95616, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Palandoken
authors.forename: Kolbot
authors.initials: K
authors.lastname: By
authors.forename: Manu
authors.initials: M
authors.lastname: Hegde
authors.forename: William R
authors.initials: WR
authors.lastname: Harley
authors.forename: Fredric A
authors.initials: FA
authors.lastname: Gorin
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nantz
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011355:Prodrugs; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride