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NEUROPHARMACOLOGY

Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition

Department of Chemistry (H.P., K.B., M.H.N.) and Department of Neurology and the Center for Neuroscience (M.H., W.R.H., F.A.G.), University of California, Davis, California

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.

Address correspondence to: Dr. Fredric A. Gorin, Department of Neurology, University of California School of Medicine, Davis, CA 95616. E-mail: fagorin{at}ucdavis.edu