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. 1975 Feb;72(2):563–566. doi: 10.1073/pnas.72.2.563

Contribution of the peptide backbone to the action of oxytocin analogs.

O Hechter, T Kato, S H Nakagawa, F Yang, G Flouret
PMCID: PMC432353  PMID: 164658

Abstract

This investigation was undertaken to evaluate the functional contribution of the peptide backbone of oxytocin in its interaction with receptor. Corey-Pauling-Koltun models of (Gly-7) deaminooxytocin, deaminotocinamide, and their respective retro-D-analogs built in any specific conformation (e.g., the Walter-Urry model for oxytocin) have a quai-equivalent topochemical arrangement of amino-acid side chains; however, the CO and NH elements of the peptide backbone of the retro-D-analog are reversed. The retro-D-analogs of deaminotocinamide and (Gly-7) deaminooxytocin (prepared using D-alle for L-Ile) and their respective N-formyl derivatives were assayed for uterotonic activity relative to related L-peptides. All retro-D-analogs (tested at concentrations ranging from 10-10 to 10-5 M) were devoid of angonistic (or antagonistic) activity in the isolated rat uterus, except for the retro-D-(D-alle-3, Gly-7) deaminooxytocinamine, which retains a terminal NH-2 group on the tail; the latter is a partial agonist with very low affinity. The results obtained with retro-D-analogs indicate that one or more of the elements of the peptide backbone of the tocinamide ring are essential for "occupation" and "activation" of uterine receptors. Oxytocin action may be the resultant of multiple hydrogen-bonding interactions between CO, NH, NH-2, and OH groups of the hormone with complementary groups on receptor, made possible by appropriate hydrophobic bonding.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BODANSZKY M. Synthesis of peptides by aminolysis of nitrophenyl esters. Nature. 1955 Apr 16;175(4459):685–685. doi: 10.1038/175685a0. [DOI] [PubMed] [Google Scholar]
  2. Brewster A. I., Hruby V. J. 300-MHz nuclear magnetic resonance study of oxytocin aqueous solution: conformational implications. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3806–3809. doi: 10.1073/pnas.70.12.3806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chan W. Y., Kelley N. A pharmacologic analysis of the significance of the chemical functional groups of oxytocin to its oxytocic activity and on the effect of magnesium on the in vitro and in vivo oxytocic activity of neurohypophysial hormones. J Pharmacol Exp Ther. 1967 Apr;156(1):150–158. [PubMed] [Google Scholar]
  4. Ferrier B. M., Jarvis D., Du Vigneaud V. Deamino-oxytocin. Its isolation by partition chromatography on Sephadex and crystallization from water, and its biological activities. J Biol Chem. 1965 Nov;240(11):4264–4266. [PubMed] [Google Scholar]
  5. Gearhart J. D., MacIntyre R. J. Lack of intercellular suppression of position-effect variegation by supernumerary Y chromosomes during cell differentiation in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1971 Jan;68(1):13–15. doi: 10.1073/pnas.68.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hase S., Walter R. Symmetrical disulfide bonds as S-protecting groups and their cleavage by dithiothreitol: synthesis of oxytocin with high biological activity. Int J Pept Protein Res. 1973;5(4):283–288. doi: 10.1111/j.1399-3011.1973.tb03463.x. [DOI] [PubMed] [Google Scholar]
  7. Hechter O., Calek A., Jr Principles of hormone action: the problem of molecular linguistics. Acta Endocrinol Suppl (Copenh) 1974;191:39–66. [PubMed] [Google Scholar]
  8. Honig B., Kabat E. A., Katz L., Levinthal C., Wu T. T. Model-building of neurohypophyseal hormones. J Mol Biol. 1973 Oct 25;80(2):277–295. doi: 10.1016/0022-2836(73)90173-3. [DOI] [PubMed] [Google Scholar]
  9. Hruby V. J., Ferger M. F., Du Vigneaud V. Synthesis and pharmacological properties of deaminotocinamide and a new synthesis of tocinamide. J Am Chem Soc. 1971 Oct 20;93(12):5539–5542. doi: 10.1021/ja00750a037. [DOI] [PubMed] [Google Scholar]
  10. MUNSICK R. A. Effect of magnesium ion on the response of the rat uterus to neurohypophysial hormones and analogues. Endocrinology. 1960 Mar;6:451–457. doi: 10.1210/endo-66-3-451. [DOI] [PubMed] [Google Scholar]
  11. PORATH J., FLODIN P. Gel filtration: a method for desalting and group separation. Nature. 1959 Jun 13;183(4676):1657–1659. doi: 10.1038/1831657a0. [DOI] [PubMed] [Google Scholar]
  12. Shemyakin M. M., Ovchinnikov Y. A., Ivanov V. T., Ryabova I. D. Topochemical approach to the structure-activity relation. Retroenantio-gly5, 10-gramicidin S. Experientia. 1967 May 15;23(5):326–326. doi: 10.1007/BF02144491. [DOI] [PubMed] [Google Scholar]
  13. Shemyakin M. M., Ovchinnikov Y. A., Ivanov V. T. Topochemical investigations of peptide systems. Angew Chem Int Ed Engl. 1969 Jul;8(7):492–499. doi: 10.1002/anie.196904921. [DOI] [PubMed] [Google Scholar]
  14. Urry D. W., Walter R. Proposed conformation of oxytocin in solution. Proc Natl Acad Sci U S A. 1971 May;68(5):956–958. doi: 10.1073/pnas.68.5.956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Vogler K., Lanz P., Lergier W., Haefely W. Synthesen von Bradykinin-Analogen mit D-Aminosäuren (all-D-Bradykinin und all-D-retro-Bradikinin) Helv Chim Acta. 1966 Jan 22;49:390–403. [PubMed] [Google Scholar]
  16. Walter R., Yamanaka T., Sakakibara S. A neurohypophyseal hormone analog with selective oxytocin-like activities and resistance to enzymatic inactivation: an approach to the design of peptide drugs. Proc Natl Acad Sci U S A. 1974 May;71(5):1901–1905. doi: 10.1073/pnas.71.5.1901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Wieland T., Penke B., Birr C. Uber Antamanid. XVI. All-D-retro-Antamanid und D-Tyr 6 -all-D-retro-antamanid. Justus Liebigs Ann Chem. 1972 May;759:71–75. doi: 10.1002/jlac.19727590105. [DOI] [PubMed] [Google Scholar]
  18. YAMASHIRO D. PARTITION CHROMATOGRAPHY OF OXYTOCIN ON 'SEPHADEX'. Nature. 1964 Jan 4;201:76–77. doi: 10.1038/201076a0. [DOI] [PubMed] [Google Scholar]

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