Somatostatin analogs which define the role of the lysine-9 amino group

Structure‐activity studies of the lysine residue in the highly active cyclic hexapeptide somatostatin analog cyclo(Pro‐Phe‐D‐Trp‐Lys‐Thr‐Phe) confirm the importance of the lysine amino group for biological activity through the loss of activity seen on replacement of lysine by ornithine, arginine, histidine and p‐amino phenylalanine. Three analogs containing thialysine, γ‐ and δ‐fluorolysine were equipotent to the parent as inhibitors of insulin, glucagon, and growth hormone release. The pKa's of the amino groups in these equiactive peptides ranged from 8.23–9.4. The lack of a correlation between the basicity of the amino groups and the biological activities suggests that deprotonation is not required for biological activity.