Tissue plasminogen activator enhancing activity of vasopressin analogues in monkeys: structure-activity study

Marmocets were used in a structure activity study of the ability of vasopressin 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.