Structure-activity and structure-binding studies of des-Asp(1)-angiotensin I analogues on the rabbit pulmonary artery.

Structural modification of des-aspartate-angiotensin I (DAA-I), a pharmacologically active peptide, affected its actions on the precontracted cardiac and pulmonary sections of the rabbit pulmonary artery. The displacement of [125I]-Sar(1)-Ile(8)-angiotensin II by the DAA-I analogues from membrane homogenates of the whole pulmonary artery was also markedly reduced. Analogues that retained similar responses as DAA-I in the functional assays exhibited binding affinities of similar magnitude as DAA-I. Analogues that had no effect in the functional assay showed markedly reduced binding affinities. The first and fifth positions on DAA-I were identified as critical positions for activity as the replacement of Arg(2) and His(6) at these positions with alanine completely abolished activity and sharply reduced binding affinities. In contrast, the last two N-terminal amino acids of DAA-I can be modified substantially (D-amino acid and alanine substitution) without loss of activity or binding affinity. The identification of critical and noncritical amino acids would offer useful leads in the design of specific DAA-I antagonists.