We report the conformational analysis by 1 H nmr in DMSO and computer simulations involving distance geometry and molecular dynamics simulations of analogs of the cyclic octapeptide D-Phe 1 -c[Cys 2 -Phe 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 ]-Thr 8 -ol (sandostatin, octreotide). The analogs D-Phe 1 -c[Cys 2 -Phe 3 -D-Trp 4 -Lys 5 -Xaa 6 -Cys 7 ]-Xbb 8 -NH 2 (Xaa ϭ allo-Thr, D-allo-Thr , D--Hyv, -Hyv, D-Thr, and Xbb ϭ Thr or Xaa ϭ Thr and Xbb ϭ allo-Thr, D-allo-Thr , -Hyv, D-Thr ) contain stereochemical changes in the Thr residues in positions 6 and 8, which allow us to investigate the influence of the stereochemistry within these residues on conformation and binding affinity. The molecular dynamics simulations provide insight into the conformational flexibility of these analogs. The compounds with (S)-configuration at the C ␣ of residue 6 adopt -sheet structures containing a type IIЈ -turn with D-Trp in the iϩ1 position, and these conformations are "folded" about residues 6 and 3. The structures are very similar to those observed for sandostatin, and the disulfide bridge results in a close proximity of the H ␣ protons of residues 7 and 2, which confirms earlier observations that a disulfide bridge is a good mimic for a cis peptide bond. The compounds with (R)-configuration at the C ␣ of residue 6 adopt considerably different backbone conformations. The structures observed for these analogs contain either a -turn about residue Lys and Xaa 6 or a ␥-turn about the Xaa 6 residue. These compounds do not exhibit significant binding to the somatostatin receptors, while the compounds with (S) configuration in position 6 bind potently to the sst2, 3, and 5 receptors. The nmr spectra of analogs with (R) or (S) configuration at the C ␣ of residue 8 are strikingly similar to each other. We have demonstrated that the chemical shifts of protons of residues 3, 4, 5, and 6, which are part of the type IIЈ -turn, and especially the effect on the Lys ␥-protons are considerably different in active molecules as compared to inactive analogs. Since the presence of a type IIЈ -turn is crucial for the binding to the receptors, the chemical shifts, the amide temperature coefficients of the Thr residue and the medium strength NOE between LysNH and ThrNH can be extremely useful as an initial screening tool to separate the active molecules from inactive analogs.