Structure-activity relationships of novel peptides related to the antiarrhythmic peptide AAP10 which reduce the dispersion of epicardial action potential duration

We report the first study on short peptide structure-activity relationships (SAR) for the antiarrhythmic peptide AAP10 and its putative receptor. Synt hetic improvements on the natural antiarrhythmic peptide AAPnat (H-Gly-Pro- Hyp-Gly-Ala-Gly) isolated from bovine atria led us to the synthesis of our lead molecule AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-NH2) which reduces dispersio n of epicardial potential duration and acts antiarrhythmically in isolated rabbit hearts. The aim of our study was to elucidate structure-activity rel ationships for AAP10 based on Langendorff experiments and molecular modelin g. Mutation of the amino acid sequence led to 11 different peptides which w ere tested analogous to the lead molecule. Among these new synthetic peptid es various including the cyclopeptide cAAP10RG, cyclo[CF3C(OH)-Gly-Ala-Gly- Hyp-Pro-Tyr] showed promising activities. (supported by the DFG and Koln-Fo rtune) (C) 2001 Elsevier Science Inc. All rights reserved.