Arginine-vasopressin analogues with high antidiuretic/vasopressor selectivity. Synthesis, biological activity, and receptor binding affinity of arginine-vasopressin analogues with substitutions in positions 1, 2, 4, 7, and 8

In a search for more selective agonists of arginine-vasopressin (AVP), 10 analogues of [Sar7]- and [MeLa7]AVP with additional substitutions in positions 1 (beta-mercaptopropionic acid), 2 (phenylalanine), 4 (valine), or 8 (D-arginine) were synthesized and tested for antidiuretic and vasopressor activities. All analogues are characterized by a relatively high antidiuretic activity and by a sharp decrease in pressor activity. Their antidiuretic/vasopressor (A/P) selectivities were 2-3 orders higher (except for peptides 2 and 3) than that of the parent hormone. The additivity of the effects of changes in positions 1, 2, 4, and 8 combined with the sarcosine or N-methylalanine substitutions in position 7 on the biological activity is observed. Binding affinities of AVP analogues to plasma membranes from bovine kidney inner medulla and from rat liver containing specific vasopressin receptors were also determined. Generally, these analogues retained high binding affinities to renal vasopressin receptors, and on the other hand they are characterized by a large decrease in binding affinities to hepatic vasopressin receptors, which share characteristics with vasopressor receptors.