Foreword by Paul Rivier

Rivier, Paul

doi:10.1017/cbo9780511779916.001

Cited by 10 publications

(11 citation statements)

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“…60.6, and 42.6 times more active. Structure-activity stud-ies have demonstrated that the amino-terminal region is required for the GH-releasing activity (2,3). In addition, MZ-3-149 had prolonged GH-releasing activity as compared to the standard, and proved to be more potent than MZ-2-51, the tnost active member of our previous series (8,9).…”

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confidence: 84%

Potent agonists of growth hormone‐releasing hormone

Zarándi¹,

Serfózó

Zsigo

et al. 1992

International Journal of Peptide and Protein Research

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Analogs of the 29 amino acid sequence of growth hormone-releasing hormone (GH-RH) with agmatine (Agni) in position 29 have been synthesized by the solid phase method, purified, and tested in itfro and in i i i~i .The majority of the analogs contained desaminotyrosine (Dat) in position I , but a few of them had Tyrl, or N-MeTyr'. Some peptides contained one or more additional L-or D-amino acid substitutions in positions 2. 12. 15, 21, 27, and/or 28. Compared to the natural sequence of GH-RH(1-29)NHz, [Dat',Ala15]GH-RH(1-28)Agm (MZ-3-191) and [~-Ala*,Ala'~]GH-RH(1-28)Agm (MZ-3-201) were 8.2 and 7.1 times more potent iri vitro, respectively. These two peptides contained Metz7. Their Nle'7 analogs. [ Dat',Ala1s,Nle'7]GH-RH( 1-2S)Agm (MZ-2-51), prepared previously (9), and [ D -A~~' , A~~~~, N I~~* ] G H -R H ( 1-28)Agm (MZ-3-195) showed relative if7 iitro potencies of 10.5 and 2.4, respectively. These data indicate that replacement of Met'' by NleZ7 enhanced the GH-releasing activity of the analog when the nlolecule contained Dat1-Ala2 residues at the N-terminus, but peptides containing Tyr'-D-Ala' in addition to Nle27 showed decreased potencies. Replacement of Ser28 with Asp in multi-substituted analogs of GH-RH(1-28)Agm resulted in a decrease in in r i m potencies compared to the parent compound. Thus, the Ser'kontaining MZ-2-5 1, and [ Dat',Alali.D-Lys",NleZ7]GH-RH( 1-28)Agm, its Asp2* homolog (MZ-3-149), possessed relative activities of 10.5 and 5.6, respectively. In iivo after the iv injection, the analogs [ Dat',Ala15,Nle'7,Asp2X]GH-RH( 1-28)Agm (MZ-3-149), [ Dat', Ala'5]GH-RH( 1-28)Agm, (MZ-3-191) and [ D -A~~' , A~~'~] G H -R H ( 1-28)Agm (MZ-3-201) showed a potency equivalent to 7.6, 4.9 and 3.3 times that of GH-RH( 1-29)NH2, respectively, at 5 min and 20.3, 4.3 and 1.7 times higher, respectively, at 15 min. After sc administration, analogs MZ-3-149, were shown to be 63.7, 55.2 and 56.8 times more potent than the parent hormone at 15 min and 57.6. 60.6, and 42.6 times more active. respectively, at 30 min. In addition, MZ-3-149 had prolonged GH-releasing activity as compared to the standard, and proved to be more potent than MZ-2-51, the tnost active member of our previous series (8,9). Our studies indicate that very potent GH-RH analogs can result from the combination of agmatine in position 29 with other substitutions. K q M D Y~T : growth hormone-releasing hormone: GH-RH analogs: solid phase peptide synthesis; structure-activity relationships Growth hormone-releasing hormone (GH-RH) exists in different molecular forms, such as GH-RH( 1-44)NHz (1) and GH-RH( 1-40)OH (2). Structure-activity stud-ies have demonstrated that the amino-terminal region is required for the GH-releasing activity (2, 3). It has been observed that replacement of Tyr' by desNH2-' Present address: Department of medical chemistry, Albert Szent-Gyorgyi Medical School, H-6720 Szeged, Hungary. Abbreviations of the amino acids are in accordance with the recommendations of the IUPAC-IUB JCBN ( J . Biol. Chem. 264.668473:

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confidence: 84%

Potent agonists of growth hormone‐releasing hormone

Zarándi¹,

Serfózó

Zsigo

et al. 1992

International Journal of Peptide and Protein Research

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“…The completed peptide was deprotected and cleaved from the resin using the low-high hydrogen fluoride technique (19) and purified by preparative C18 RP-HPLC chromatography (20) with an acetonitrile/O. 1 M ammonium acetate pH 6.5 gradient to >98% homogeneity (the integrated area under the peptide peak vs the total integrated area recorded at 210nm) based on analytical C18 RP-HPLC with 0 .…”

Section: Leu-ile-asp-ser-phe-gln-glu-ile-val-lys-glu-val-mentioning

confidence: 99%

An improved solid‐phase synthesis of a difficult‐sequence peptide using hexafluoro‐2‐propanol

Milton

1990

International Journal of Peptide and Protein Research

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The polar solvent 1,1,1,3,3,3‐hexafluoro‐2‐propanol was used, diluted with dichloromethane, to improve the extent and time of aminoacylation and acetylation in the solid‐phase synthesis of a difficult‐sequence peptide (the d‐Ala17 analog of the human gonadotropin‐releasing hormone precursor peptide fragment 14‐36) which characteristically exhibits chronic repetitive incomplete peptide bond formation.

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“…Structure-activity studies with analogs of human growth hormone-releasing factor (GRF) (1,2) have shown that the aminoterminal region is required for biological ac-*Present address: INRS-Sante, Unwersite du Quebec, 245, Boul. Hymus, Pointe-Claire, Quebec H9R 1G6, Canada Abbreviations follow the recommendations of the IUPAC-IUB Commission on Biochemical Nomenclature [Biochem.…”

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confidence: 99%

“…126, 773-780 (1972)l. Additional abbreviations: DCC, dicyclohexylcarbodiimide; HOBt, hydroxybenzotriazole; DMF, dimethylformamide; BOP, benzotriazol-I-yl-oxy-tris-(dimethy1amino)phosphonium hexafluorophosphate; DIEA, diisopropyl-tivity (1,3). The presence of an aromatic residue at position-I has also been shown to be a requirement for full receptor-ligand interaction (4).…”

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confidence: 99%

Synthesis, biological activity and conformational analysis of cyclic GRF analogs

Félix¹,

Heimer²,

Wang³

et al. 1988

International Journal of Peptide and Protein Research

201

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A novel cyclic GRF analog, cyclo(Asp8‐Lys12)‐[Asp8,Ala15]‐GRF(1‐29)‐NH2, i.e. cyclo8.12[Asp8,Ala15]‐GRF(1‐29)‐NH2, was synthesized by the solid phase procedure and found to retain significant biological activity. Solid phase cyclization of Asp8 to Lys12 proceeded rapidly (∼2h) using the BOP reagent. Substitution of Ala12 with d‐Ala2 and/or NH2‐terminal replacement (desNH2‐Tyr1 or N‐MeTyr1) in the cyclo8.12[Asp8,Ala15]‐GRF(1‐29)‐NH2 system resulted in highly potent analogs that were also active in vivo. Conformational analysis (circular dichroism and molecular dynamics calculations based on NOE‐derived distance constraints) demonstrated that cyclo8.12[Asp8,Ala15]‐GRF(1‐29)‐NH2 contains a long α‐helical segment even in aqueous solution. A series of cyclo8.12 stereoisomers containing d‐Asp8 and/or d‐Lys12 were prepared and also found to be highly potent and to retain significant α‐helical conformation. The high biological activity of cyclo8.12[N‐MeTyr1,d‐Ala2,Asp8,Ala15]‐GRF(1‐29)‐NH2 may be explained on the basis of retention of a preferred bioactive conformation.

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Foreword by Paul Rivier

Cited by 10 publications

References 0 publications

Potent agonists of growth hormone‐releasing hormone

Potent agonists of growth hormone‐releasing hormone

An improved solid‐phase synthesis of a difficult‐sequence peptide using hexafluoro‐2‐propanol

Synthesis, biological activity and conformational analysis of cyclic GRF analogs

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