Structure-activity relationships in the C-terminal part of luteinizing hormone releasing hormone (LH-RH)

Fujino, Masahiko; Kobayashi, Shigeru; Obayashi, M.; Shinagawa, Susumu; Fukuda, Tsunehiko; Kitada, Chieko; Nakayama, Ryo; Yamazaki, Iwao; White, W. F.; Rippel, R. H.

doi:10.1016/0006-291x(72)90490-1

Cited by 137 publications

(45 citation statements)

References 8 publications

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“…The decapeptide of LH-RH and the nanopeplamide], (TAP-031) were synthesized by Fujino et al (1972) of Takeda Pharmaceutical Co., Osaka, Japan. Figure 5 and Figure 6.…”

Section: Methodsmentioning

confidence: 99%

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A New More Potent Analogue of LH-RH

Taya

Igarashi

1974

Endocrinol Japon

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“…The decapeptide of LH-RH and the nanopeplamide], (TAP-031) were synthesized by Fujino et al (1972) of Takeda Pharmaceutical Co., Osaka, Japan. Figure 5 and Figure 6.…”

Section: Methodsmentioning

confidence: 99%

“…These synthetic analogues of LH-RH had no or far less activity than natural LH-RH. However, Fujino et al (1972) reported a new analogue of LH-RH having LH-RH in the LH-RH activity assayed by the ovulation-induction method.…”

mentioning

confidence: 99%

A New More Potent Analogue of LH-RH

Taya

Igarashi

1974

Endocrinol Japon

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“…Removal of the amide to yield the free acid of GnRH results in very low activity (150). This has recently been confirmed for the human GnRH receptor expressed in COS-1 cells (67).…”

Section: The Cooh-terminal Domain (Pro-gly⅐nh 2 )mentioning

confidence: 66%

Molecular Mechanisms of Ligand Interaction with the Gonadotropin-Releasing Hormone Receptor

Sealfon

1997

Endocrine Reviews

131

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“…With few exceptions (7,8), these shortened analogs had low LH-RH agonistic activity. To evaluate in vitro potencies and to study the structureactivity relationships, 29 hexapeptide and heptapeptide analogs with agonistic or antagonistic activity were synthesized by Haviv et al (10) and antagonistic activity is influenced by substituents in these positions.…”

Section: Discussionmentioning

confidence: 99%

“…They found that these peptides had only marginal activity, except for [des-Gly10]LH-RH, which had 10%6 activity of the parent hormone. Although the free acid analogue of LH-RH exhibited very low potency, replacement of the C-terminal Gly-NH2 with alkylamides resulted in peptides significantly more active than LH-RH itself (7,8). Sandow and Konig (9) examined fragments of LH-RH agonist buserelin ([DSer(OBu9)6,Pro9-NHEtJLH-RH where OBu' is t-butoxy), and they found buserelin-(3-9) to be the smallest fragment possessing significant ovulatory activity.…”

mentioning

confidence: 99%

Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties.

Janáky

Juhász

Rékási

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Five hexapeptide and heptapeptide analogs of luteiniSng hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhanc target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were anidated with ethylamine and acylated on the N termi- More than 2500 agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH) have been synthesized since the discovery and structural elucidation (1) of LH-RH in view of their expected medical application (2-4). In addition to the various endocrine and gynecological applications of some of these analogs, they may be potential therapeutic agents in the treatment of hormone-sensitive tumors, like prostate cancer and breast cancer.The synthetic effort was directed toward finding potent agonists and antagonists by changing amino acids at certain positions, using D-form and/or unusual amino acids. However, only a few reports deal with analogs with shortened LH-RH peptide chain. Deletion of N-or C-terminal amino acids causes a dramatic loss of activity. In 1973-1974) synthesized a series of short-chain LH-RH analogs to find the smallest fragments biologically active by shortening the decapeptide sequence first at the N terminal and, in another series, shortening it at the C terminal. They found that these peptides had only marginal activity, except for [des-Gly10]LH-RH, which had 10%6 activity of the parent hormone. Although the free acid analogue of LH-RH exhibited very low potency, replacement of the C-terminal Gly-NH2 with alkylamides resulted in peptides significantly more active than LH-RH itself (7,8). Sandow and Konig (9) examined fragments of LH-RH agonist buserelin ([DSer(OBu9)6,Pro9-NHEtJLH-RH where OBu' is t-butoxy), and they found buserelin-(3-9) to be the smallest fragment possessing significant ovulatory activity. Recently, Haviv et al.(10) synthesized and tested several reduced-size hexapeptide analogs. Their results showed a wide range of binding affinities (equal to or even exceeding that of LH-RH) to pituitary cell membrane. Depending on the nature of the substituent in positions 4 and 6, the biological responses could be agonistic or antagonistic. Some of their peptides exerted significant antagonistic effect. They suggested that these LH-RH-(4-9) analogs may become useful agents in the treatment of various endocrine disorders.LH-RH agonists and antagonists with high binding affinity to human breast cancer cell membrane can serve as carriers for cytotoxic compounds (11-13) and target the chemotherapeutic agents to the receptors of cancerous tissues. In the present paper we report the synthesis ofreduced-size LH-RH analogs carrying various cytotoxic alkylating agents, anthraquinone derivatives, antimetabolite methotrexate (MTX), and Cisplatin (cis-diamminedichloroplatinum)-like platinum complex (Fig. 1). MATERIALS AND METHODSPrecursor Peptides. Reduced-size LH-RH analogs wer...

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Structure-activity relationships in the C-terminal part of luteinizing hormone releasing hormone (LH-RH)

Cited by 137 publications

References 8 publications

A New More Potent Analogue of LH-RH

A New More Potent Analogue of LH-RH

Molecular Mechanisms of Ligand Interaction with the Gonadotropin-Releasing Hormone Receptor

Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties.

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