Antagonistic analogs in GH-RH inhibiting IGF-I and -II

A compound, R12 technology, applied in the field of new synthetic peptides, government-funded, can solve the problem of inferior antagonist properties

Inactive Publication Date: 2001-12-26
THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is said that [Ser 9 -ψ[CH 2 -NH]-Tyr 10 ]hGH-RH(1-29) has less antagonistic properties than the standard antagonist [N-Ac-Tyr 1 , D-Arg 2 ]GH-RH(1-29)-NH 2

Method used

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  • Antagonistic analogs in GH-RH inhibiting IGF-I and -II
  • Antagonistic analogs in GH-RH inhibiting IGF-I and -II
  • Antagonistic analogs in GH-RH inhibiting IGF-I and -II

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0125] Example IPhAc 0 -Tyr 1 -D-Arg 2 -Asp 3 -Ala 4 -Ile 5 -Phe(pCl) 6 -Thr 7 -Asn 8 -Arg 9 -Tyr 10 -Arg 11 -Lys 12 -Val 13 -Leu 14 -Abu 15 -Gln 16 -Leu 17 -Ser 18 -Ala 19 -Arg 20 -Lys 21 -Leu 22 -Leu 23 -Gln 24 -Asp 25 -Ile 26 -Nle 27 -D-Arg 28 -Har 29 -NH 2 (peptide 1){[PhAc 0 , D-Arg 2 , Phe(pCl) 6 , Arg 9 , Abu 15 , Nle 27, D-Arg 28 , Har 29 ]hGH-RH(1-29)NH 2}

[0126] The synthesis of this peptide was carried out in a step-by-step manner using a manually operated solid-phase peptide synthesis device. Briefly, following the scheme described in Table 1 with CH 2 Cl 2 Para-methylbenzhydrylamine (MBHA) resin (Bachem, California) (720 mg, 0.50 mmole) was neutralized with formulated 5% DIEA and washed. In a manually operated solid-phase peptide synthesizer, the DMF-CH 2 Cl 2 (1:1) prepared Boc-Har (NO 2 )-OH (500 mg, 1.5 mmole) solution was shaken with the neutralized resin and DIC (235 μl, 1.5 mmole) for 1 hour. Aft...

Embodiment III

[0150] Embodiment III biological activity:

[0151] The peptides of the invention were tested in in vitro and in vivo assays to determine their inhibition of hGH-RH(1-29)NH 2 Ability to induce GH release. Hypocooled rat pituitary system:

[0152] These peptide analogs were tested according to a modification (Z. Rekasi and A.V. Schally, P.N.A.S. 90: 2146-2148, 1993) of an assay previously described (S. Vigh and A.V. Schally, Peptide 5: 241-347, 1984). In vitro assays were performed.

[0153] Briefly, cells were pre-incubated with various concentrations of peptides (3ml) for 9 minutes. Add 1nM hGH-RH(1-29)NH immediately after incubation 2 (1 ml) for 3 minutes [0 minute response]. To examine the duration of the antagonistic effect of this analogue, 1 nM hGH-RH(1-29)NH was added after 30, 60, 90 and 120 minutes 2 , for 3 minutes [30, 60, 90, 120 minute responses]. The net integer value of the GH response was estimated. Compare GH responses with 1 nM hGH-RH(...

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Abstract

A series of novel synthetic analogs of hGH-RH(1-29)NH2 are provided herein. These analogs inhibit the activity of endogenous hGH-RH, thus hindering the release of growth hormone. Compared with the previously described analogs, the stronger inhibitory ability of the novel analogs is due to multiple amino acid substitutions.

Description

field of invention [0001] This invention was made in part with government support from the Medical Research Division of the Bureau of Veterans Affairs. The government has certain rights in this application. [0002] This invention relates to novel synthetic peptides which inhibit the release of growth hormone from the pituitary gland in mammals, and to therapeutic compositions containing the novel peptides. Background of the invention [0003] Growth hormone ("GH") is a 191 amino acid peptide that stimulates the production of several different growth factors such as insulin-like growth factor I (IGF-I), and thus stimulates the production of various tissues (bone, connective tissue, Muscle and internal organs) growth, and cause some physiological activities (promote nucleic acid and protein synthesis and lipolysis, but reduce urea secretion). [0004] GH release is controlled by release and inhibitory factors secreted by the hypothalamus. The major re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K38/27A61P5/08A61P35/00C07K14/60
CPCA61K38/00C07K14/60A61P35/00A61P5/04A61P5/06A61P5/08
Inventor A·V·沙利J·瓦格加M·扎兰蒂
Owner THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
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