Insertion of an electronegative sulfur atom in the side chain of position 5 of angiotensin II: changes in the tachyphylactic properties of the peptide

Angiotensin II (All) analogs bearing n-Leu, Met or S-substituted groups for cysteine at position 5 were studied regarding their agonistic and tachyphy lactic properties. It was shown that these analogs lowered the relative aff inity towards the AT(1) receptor as determined by contractile responses, wh ich could be due to the removal of the beta-branching residue at position 5 . Insertion of a sulfur atom in a different position away from the attached backbone carbon atom presented no significant difference in EC50 values fo r these analogs. Interestingly, the S-bearing analogs at position 5 were fu ll agonists but the tachyphylactic property was lost, in contrast to [n-Leu (5)]All, which still induced reduction of the contractile responses. Nevert heless after replacing the Asp with Sar in position 1 (Sar(1)) tachyphylaxi s was again established. It is concluded that the insertion of Met or an S- substituted cysteine into the side chain at position 5 of All may promote i nteractions with its receptor due to the slight electronegative character o f the sulfur atom and changes in the restricted conformational freedom of t he lle(5) residue in the All molecule. This was overcome by Sar(1), probabl y through interactions due to its fully protonated N-terminal amino group a nd favoring the conformation responsible for the tachyphylaxis phenomenon.