Synthesis and biological evaluation of antagonists of growth hormone- releasing hormone with high and protracted in vivo activities

J. L. Varga, Andrew V Schally, V. J. Csernus, M. Zarandi, G. Halmos, K. Groot, Z. Rekasi

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (α- aminobutyric acid),Nle27]hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1,D-Arg2,Phe (4-Cl)6,Arg9,Abu15,Nle27,D-Arg29] hGH-RH(1-29)NH2(JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1,D- Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr1,D-Arg2,Phe(4- Cl)6,Har9,Tyr(Me)10,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH- RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.

Original languageEnglish
Pages (from-to)692-697
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number2
DOIs
StatePublished - Jan 19 1999
Externally publishedYes

Fingerprint

Growth Hormone-Releasing Hormone
Human Growth Hormone
Hormone Antagonists
Homoarginine
Norleucine
Fenclonine
Aminobutyrates
Peptides
Insulin-Like Growth Factor II
Insulin-Like Growth Factor I
Nude Mice
Neoplasms

Keywords

  • Cancer therapy
  • Inhibitors of GH release
  • Structure-activity relationships

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Synthesis and biological evaluation of antagonists of growth hormone- releasing hormone with high and protracted in vivo activities. / Varga, J. L.; Schally, Andrew V; Csernus, V. J.; Zarandi, M.; Halmos, G.; Groot, K.; Rekasi, Z.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 2, 19.01.1999, p. 692-697.

Research output: Contribution to journalArticle

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abstract = "Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (α- aminobutyric acid),Nle27]hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1,D-Arg2,Phe (4-Cl)6,Arg9,Abu15,Nle27,D-Arg29] hGH-RH(1-29)NH2(JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1,D- Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr1,D-Arg2,Phe(4- Cl)6,Har9,Tyr(Me)10,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH- RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.",
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T1 - Synthesis and biological evaluation of antagonists of growth hormone- releasing hormone with high and protracted in vivo activities

AU - Varga, J. L.

AU - Schally, Andrew V

AU - Csernus, V. J.

AU - Zarandi, M.

AU - Halmos, G.

AU - Groot, K.

AU - Rekasi, Z.

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N2 - Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (α- aminobutyric acid),Nle27]hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1,D-Arg2,Phe (4-Cl)6,Arg9,Abu15,Nle27,D-Arg29] hGH-RH(1-29)NH2(JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1,D- Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr1,D-Arg2,Phe(4- Cl)6,Har9,Tyr(Me)10,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH- RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.

AB - Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (α- aminobutyric acid),Nle27]hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1,D-Arg2,Phe (4-Cl)6,Arg9,Abu15,Nle27,D-Arg29] hGH-RH(1-29)NH2(JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1,D- Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr1,D-Arg2,Phe(4- Cl)6,Har9,Tyr(Me)10,Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH- RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.

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KW - Inhibitors of GH release

KW - Structure-activity relationships

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