Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity.

H-DPhe(2)-c[Cys(3) -Phe(7) -DTrp(8)-Lys(9)-Thr(10)-Cys(14)] -Thr(15) -NH(2) (1) (a somatostatin agonist, SRIF numbering) and H-Cpa(2) -c[DCys(3) -Tyr(7) -DTrp(8)-Lys(9)-Thr(10)-Cys(14)] -Nal(15)-NH(2) (4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (SSt(2/3/5)) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or D-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst(s) The introduction of Hey at positions 3 and 14 improved selectivity for sst(2) as a result of significant loss of binding affinity at the other ssts. Substitution by DHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst(2) and sst(3) as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.