Synthesis and biological evaluation of superactive agonists of growth hormone-releasing hormone

Jan Izdebski, Jacek Pinski, Judit E. Horvath, Gabor Halmos, Kate Groot, Andrew V Schally

Research output: Contribution to journalArticle

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Abstract

Analogs of the 29 amino acid sequence of human growth hormone-releasing hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosine (Dat) in position 1, norleucine (Nle) in position 27, and L-α-aminobutyric acid (Abu) in position 15 have been synthesized, and their biological activity was evaluated. Some peptides contained one or two residues of ornithine (Orn) instead of Lys in positions 12 and 21 and additional replacements in positions 8 and 28. All analogs were found to be more potent than hGH-RH-(1- 291-NH2 in the superfused rat pituitary cell system. In tests in vivo in rats after subcutaneous administration, the analogs JI-22, [Dat1,Orn12,21,Abu15,Nle27, Agm29]hGH-RH-(1-29); JI-34, [Dat1,Orn12,21,Abu15,Nle27, Asp28, Agm29]hGH-RH-(1-29); JI-36, [Dat1,Thr8,Orn12,21, Abu15,Nle27,Asp28,Agm29]hGH-RH-(1-29); and JI-38, [Dat1,Gln8,Orn12,21,Abu15,Nle27,Asp28,Agm29]hGH- RH-(1-29) displayed a potency 44.6, 80.9, 95.8, and 71.4 times greater, respectively, than that of hGH-RH-(1-29)-NH2 at 15 min and 217.1, 89.7, 87.9, and 116.8 times greater at 30 min. After intravenous administration, JI-22, JI-36, and JI-38 were 3.2-3.8 times more potent than hGH-RH-(1-29)- NH2 at 5 min and 6.1-8.5 times more active at 15 min. All analogs were found to have higher binding affinities for GH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2. Because of high activity and greater stability, these analogs could be considered for therapy of patients with growth hormone deficiency.

Original languageEnglish
Pages (from-to)4872-4876
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number11
DOIs
StatePublished - May 23 1995
Externally publishedYes

Fingerprint

Growth Hormone-Releasing Hormone
Human Growth Hormone
Norleucine
Agmatine
Aminobutyrates
Ornithine
Intravenous Administration
Growth Hormone
Amino Acid Sequence
Peptides

Keywords

  • peptide synthesis
  • resistance to enzymatic degradation
  • stimulation of release of growth hormone

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Synthesis and biological evaluation of superactive agonists of growth hormone-releasing hormone. / Izdebski, Jan; Pinski, Jacek; Horvath, Judit E.; Halmos, Gabor; Groot, Kate; Schally, Andrew V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 11, 23.05.1995, p. 4872-4876.

Research output: Contribution to journalArticle

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abstract = "Analogs of the 29 amino acid sequence of human growth hormone-releasing hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosine (Dat) in position 1, norleucine (Nle) in position 27, and L-α-aminobutyric acid (Abu) in position 15 have been synthesized, and their biological activity was evaluated. Some peptides contained one or two residues of ornithine (Orn) instead of Lys in positions 12 and 21 and additional replacements in positions 8 and 28. All analogs were found to be more potent than hGH-RH-(1- 291-NH2 in the superfused rat pituitary cell system. In tests in vivo in rats after subcutaneous administration, the analogs JI-22, [Dat1,Orn12,21,Abu15,Nle27, Agm29]hGH-RH-(1-29); JI-34, [Dat1,Orn12,21,Abu15,Nle27, Asp28, Agm29]hGH-RH-(1-29); JI-36, [Dat1,Thr8,Orn12,21, Abu15,Nle27,Asp28,Agm29]hGH-RH-(1-29); and JI-38, [Dat1,Gln8,Orn12,21,Abu15,Nle27,Asp28,Agm29]hGH- RH-(1-29) displayed a potency 44.6, 80.9, 95.8, and 71.4 times greater, respectively, than that of hGH-RH-(1-29)-NH2 at 15 min and 217.1, 89.7, 87.9, and 116.8 times greater at 30 min. After intravenous administration, JI-22, JI-36, and JI-38 were 3.2-3.8 times more potent than hGH-RH-(1-29)- NH2 at 5 min and 6.1-8.5 times more active at 15 min. All analogs were found to have higher binding affinities for GH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2. Because of high activity and greater stability, these analogs could be considered for therapy of patients with growth hormone deficiency.",
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T1 - Synthesis and biological evaluation of superactive agonists of growth hormone-releasing hormone

AU - Izdebski, Jan

AU - Pinski, Jacek

AU - Horvath, Judit E.

AU - Halmos, Gabor

AU - Groot, Kate

AU - Schally, Andrew V

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N2 - Analogs of the 29 amino acid sequence of human growth hormone-releasing hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosine (Dat) in position 1, norleucine (Nle) in position 27, and L-α-aminobutyric acid (Abu) in position 15 have been synthesized, and their biological activity was evaluated. Some peptides contained one or two residues of ornithine (Orn) instead of Lys in positions 12 and 21 and additional replacements in positions 8 and 28. All analogs were found to be more potent than hGH-RH-(1- 291-NH2 in the superfused rat pituitary cell system. In tests in vivo in rats after subcutaneous administration, the analogs JI-22, [Dat1,Orn12,21,Abu15,Nle27, Agm29]hGH-RH-(1-29); JI-34, [Dat1,Orn12,21,Abu15,Nle27, Asp28, Agm29]hGH-RH-(1-29); JI-36, [Dat1,Thr8,Orn12,21, Abu15,Nle27,Asp28,Agm29]hGH-RH-(1-29); and JI-38, [Dat1,Gln8,Orn12,21,Abu15,Nle27,Asp28,Agm29]hGH- RH-(1-29) displayed a potency 44.6, 80.9, 95.8, and 71.4 times greater, respectively, than that of hGH-RH-(1-29)-NH2 at 15 min and 217.1, 89.7, 87.9, and 116.8 times greater at 30 min. After intravenous administration, JI-22, JI-36, and JI-38 were 3.2-3.8 times more potent than hGH-RH-(1-29)- NH2 at 5 min and 6.1-8.5 times more active at 15 min. All analogs were found to have higher binding affinities for GH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2. Because of high activity and greater stability, these analogs could be considered for therapy of patients with growth hormone deficiency.

AB - Analogs of the 29 amino acid sequence of human growth hormone-releasing hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosine (Dat) in position 1, norleucine (Nle) in position 27, and L-α-aminobutyric acid (Abu) in position 15 have been synthesized, and their biological activity was evaluated. Some peptides contained one or two residues of ornithine (Orn) instead of Lys in positions 12 and 21 and additional replacements in positions 8 and 28. All analogs were found to be more potent than hGH-RH-(1- 291-NH2 in the superfused rat pituitary cell system. In tests in vivo in rats after subcutaneous administration, the analogs JI-22, [Dat1,Orn12,21,Abu15,Nle27, Agm29]hGH-RH-(1-29); JI-34, [Dat1,Orn12,21,Abu15,Nle27, Asp28, Agm29]hGH-RH-(1-29); JI-36, [Dat1,Thr8,Orn12,21, Abu15,Nle27,Asp28,Agm29]hGH-RH-(1-29); and JI-38, [Dat1,Gln8,Orn12,21,Abu15,Nle27,Asp28,Agm29]hGH- RH-(1-29) displayed a potency 44.6, 80.9, 95.8, and 71.4 times greater, respectively, than that of hGH-RH-(1-29)-NH2 at 15 min and 217.1, 89.7, 87.9, and 116.8 times greater at 30 min. After intravenous administration, JI-22, JI-36, and JI-38 were 3.2-3.8 times more potent than hGH-RH-(1-29)- NH2 at 5 min and 6.1-8.5 times more active at 15 min. All analogs were found to have higher binding affinities for GH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2. Because of high activity and greater stability, these analogs could be considered for therapy of patients with growth hormone deficiency.

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