Superactive octapeptide somatostatin analogs containing tryptophan at position 1

We synthesized a series of octapeptide analogs of somatostatin, containing N-terminal tryptophan or another amino acid followed by the hexapeptide sequences (Cys-Phe-D-Trp-Lys-Thr-Cys) or (Cys-Tyr-D-Trp-Lys-Val-Cys) and a C-terminal threoninamide or tryptophanamide. After purification by HPLC, the inhibitory activities of these analogs on the release of growth hormone (somatotropin) in rats were determined in vivo. The eight octapeptides with an N-terminal tryptophan residue were found to have a greater inhibitory effect than somatostatin. The most potent of these analogs, D-Trp-(Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, was 94.3 times more active than somatostatin. The other analogs, in order of decreasing potency, were Ac-Trp-(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr-NH₂, D-Trp(For)-(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr-NH₂, D-Trp-(Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH₂, Ac-Trp(For)-(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr-NH₂, Ac-Trp-(Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH₂, D-Trp-(Cys-Phe-D-Trp-Lys-Thr-Cys)-Trp-NH₂, and D-Trp-(Cys-Tyr-D-Trp-Lys-Val-Cys)-Trp-NH₂. The growth hormone inhibitory activity of these analogs was from 53.7 to 11.6 times greater than that of somatostatin. The octapeptides containing D- or L-tryptophan at the N-terminus, phenylalaine at position 3, and threonine at position 6 exhibited a greater inhibitory effect on growth hormone release than that of the analogs with tyrosine and valine at positions 3 and 6, respectively. Substitution of D-tryptophan for D-phenylalanine at the N-terminus in the octapeptide containing phenylalanine in the third, threonine in the sixth, and threoninamide in the C-terminal position also increased the growth hormone-release inhibitory activity. Time-Course assay showed that D-Trp-(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr-NH₂ (RC-98-I), in a dose of 1 μg/kg of body weight, inhibited the release of growth hormone for at least 3 hr. In view of their high activity and prolonged duration of action, some of these analogs could be useful clinically.