Bradykinin and angiotensin II analogs containing a conformationally constrained proline analog

Three analogs of bradykinin and one of angiotensin II have been prepared in which the naturally occurring proline residues have been replaced by the bicyclic amino acid, 2,4-methanoproline (2,4-MePro). The relative binding affinities for these analogs were determined to be significantly reduced in the cases of the three bradykinin analogs; [2,4-MePro3]-BK retains 1.3%, [2,4-MePro7]-BK retains 0.3% and [2,4-MePro2]-BK retains 0.021% of the binding affinity of bradykinin. Results from other modification at positions three and seven indicate preference for the trans-amide bond preceding these residues implying that other factors, either steric or conformational, are responsible for the decreased affinity for the receptor seen with 2,4-MePro substitution. The retention of significant binding affinity (26%) in the case of [Ile5,2,4-MePro7]-angiotensin II gives direct evidence that the trans-conformation of the proline amide bond is the one recognized by the AII receptor. Only significant retention of activity can be interpreted unambiguously with the use of this proline analog because of its known conformational differences from Pro as well as its increased steric requirements at the receptor.