Analogs of growth hormone-releasing factor (1-29) amide containing the reduced peptide bond isostere in the N-terminal region

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Abstract
Previous peptide structure-activity investigations employing the .psi.[CH2NH] peptide bond isostere have produced antagonists when inserted into various sequences. These include bombesin, in which the incorporation of Leu13.psi.[CH2NH]Leu14 produced a potent antagonist, and tetragastrin, with which Boc-Trp-Leu.psi.[CH2NH]Asp-Phe-NH2 is an antagonist. In this study, we chose to investigate the effect of this isostere on growth hormone-releasing factor (1-29) amide. Analogues were prepared by solid-phase synthesis and the isosteres incorporated by racemization-free reductive alkylation with a preformed protected amino acid aldehyde in the presence of NaBH3CN. The aldehydes were prepared by the reduction of the protected N,O-dimethyl hydroxamates with LiAlH4 at 0.degree. C. The purified analogues were assayed in a 4-day primary culture of male rat anterior pituitary cells for growth hormone (GH) release. Potential antagonists were retested in the presence of GRF(1-29)NH2. The following results were obtained: At position 5-6, a very weak agonist was produced with .mchlt. 0.01% activity. Incorporation of the isostere in positions 1-2, 2-3, and 6-7 gave weak agonists with .apprx. 0.1% activity. Agonists with 0.39% and 1.6% activity were produced by incorporation at 10-11 and 3-4, respectively. The analogue [Ser9.psi.[CH2NH]Try10]GRF(1-29)NH2 was found to be an antagonist in the 10 .mu.M range vs 1 nM GRF and had no agonist activity at doses as high as 0.1 mM.

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