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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 27, 2004; DOI: 10.1124/jpet.104.076984

0022-3565/05/3123-961-967$20.00
JPET 312:961-967, 2005
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NEUROPHARMACOLOGY

Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition{boxs}

Hasan Palandoken, Kolbot By, Manu Hegde, William R. Harley, Fredric A. Gorin, and Michael H. Nantz

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.

Received August 31, 2004; accepted October 20, 2004.

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






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