Structure-Activity Relationships of a Synthetic Pentapeptide that Specifically Releases Growth Hormonein Vitro*

Abstract

Tyr-dTrp-Gly-Phe-Met-NH₂ is a unique synthetic Met⁵-enkephalin peptide analog that at concentrations of 1–100 μg/ml incubation medium acts directly on the pituitary of rats in vitro to release GH specifically but not LH, FSH, TSH, PRL, or ACTH. Structure-activity studies of this pentapeptide emphasize the prime importance of an aromatic amino acid residue at the 2 position for in vitro GH-releasing activity. Both Tyr-dTrp-Gly-Phe-Met-NH₂, and Tyr-dPhe-Gly-Phe-Met-NH2 released GH in vitro, while large concentrations of seven enkephalin analogs, which did not have an aromatic amino acid residue in the 2 position, had essentially no GH-releasing activity. In addition, the importance of a dTrp or dPhe rather than an lTrp or lPhe residue in the 2 position was apparent, since neither Tyr-lTrp-Gly-Phe-Met-NH₂ nor Tyr-lPhe-Gly-Phe- Met-NH₂ were active. Although the GH-releasing activity of the C-terminal nonamidated Tyr-dTrp-Gly-Phe-Met peptide was not determined, the nonamidated Tyr-dPhe-Gly-Phe-Met peptide was inactive. Morphine, Met⁵ or Leu⁵ enkephalin peptides, and several of the potent DAla², Met⁵ enkephalin amide opiate active analogs did not have in vitro GH-releasing activity. The opiate antagonist, naloxone, failed to inhibit the release of GH induced by Tyr-dTrp-Gly-Phe-Met-NH₂. Although the GH-releasing pentapeptides described lack the potency of a natural hormone, they may prove valuable for understanding the structure- activity relationships of small peptides that act directly on the pituitary to release GH. From previous experience in synthesizing analogs of the hypothalamic hypophysiotrophic hormones with increased potency, it seems likely that more potent peptides related to Tyr-dTrp-Gly-Phe-Met-NH₂ will be designed. (Endocrinology106: 663, 1980)