Analogs of atriopeptin(103-125)amide having high binding selectivity

Abstract

Analogues of atriopeptin(103-125)amide were prepared having a disulfide bridge at positions different from that found in the natural product. Most of these conformationally perturbed peptides were found to bind selectively to one subclass of binding sites. Binding affinity to a class of specific binding sites that is not associated with any known biological activity (nonvasorelaxant or NVR binding sites) is unaffected or even modestly improved. Affinity for the receptor subclass that is associated with vasorelaxation (VR subclass) decreases in most examples. In several cases, binding to the VR subclass is below the limits of detection for the assay used here. The data demonstrate that binding of atrial peptides to VR receptors requires rigidly defined receptor/ligand interactions. In contrast, the NVR subclass of binding sites appears to tolerate changes in peptide structure quite well.

Structure activity in the atrial natriuretic peptide (ANP) family

“…Enlargement of the ring to 18 residues by shifting one cysteine to the neighboring 104 or 122 position afforded analogues with equivalent binding affinity to the guanylate cyclase-coupled receptor (94) (Table V). Further enlargement to a 19-amino acid ring, by simultaneously shifting cysteines 105 and 121 to 104 and 122 position, respectively, resulted in a 100-fold decrease in binding affinity to the guanylate cyclase-coupled receptor (94) (Table VI). In other studies, ring size has been altered more significantly either by shifting of the disulfide bridge by several residues, by deleting residues within the cyclic core or by forming additional disulfide bridges (Table VII).…”