Tissue Plasminogen Activator Enhancing Activity of Vaso-Pressin Analogues in Monkeys: Structure-Activity Study

Abstract

Marmocets were used in a structure activity study of the ability of vaso-pressin analogues to activate plasminogen activator (tPA). In evaluation of dDAVP analogues with L – alanine migrating from position 2 to 9 we found [L – Ala⁴]dDAVP and [L – Ala⁵]dDAVP to be potent activators of tPA. Double substitutions in dDAVP showed that combinations of a modification in position 4 valine with a change at position 2 (2 – O – methyltyrosine) generated tPA releasing activity. On the other hand enlargement of the substituent at position 2 (2 – O – ethyltyrosine) completely eliminated the activity of [L – Val⁴]dDAVP. The tPA activity is dependent on the position of a positively charged group at the amino acid in position 8 of the peptide chain. A shift of the guanido group further away from the backbone (D – arginine to D – homoarginine) resulted in a loss of tPA activating properties.