Synthesis of the luteinizing releasing hormone of the hypothalamus and its hormonal activity

Sievertsson, Hans; Chang, Jaw‐Kang; Bogentoft, Conny; Currie, Bruce L.; Folkers, Karl; Bowers, Cyril Y.

doi:10.1016/s0006-291x(71)80265-6

Cited by 54 publications

(10 citation statements)

References 13 publications

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“…The synthesis of luteinizing hormone releasing factor (LH-RF) or releasing hormone (LH-RH) [Schally et al, 1971;Monahan el a/., 1971;Sievertsson et al, 1971;Geiger et al, 1971] enabled specific immune sera to be prepared and radioimmunoassay to be carried out [Kerdeliiue et a/., 1973;Pelletier and Dubois, 1973;Barker et al, 1973], More recently the use of antisera to synthetic LH-RH in various mammals has revealed the existence of specifically immunoreactive hypothalamic axons, the majority of which terminate in the median eminence in contact with the primary capillary plexus of the portal system [Leonardelli et al, 1973], However, because the cellular origin of these axons could not be specified in our material, we attempted to increase the LH-RH con-centration in the perikarya by stimulating its synthesis and inhibiting axonal transport. Under these conditions we were able to visualize the perikarya of specifically immunoreactive cells, mainly in the rostral hypothalamic area ( fig.…”

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confidence: 99%

Immunofluorescence Study of the Preoptico-Infundibular LH-RH Neurosecretory Pathway of the Guinea Pig During the Estrous Cycle

Barry¹,

Dubois²

1974

Neuroendocrinology

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A fluorescent antibody study of LH-RH-producing cells was made with antisera to synthetic LH-RH in normally cycling female guinea pigs and normal female guinea pigs during the first post-partum cycle. The specifically immunoreactive material, present in the distal segment of the preoptico-infundibular LH-RH neurosecretory pathway, shows significant modifications that are particularly distinct in the ventral labium of the median eminence, with a maximum concentration at the end of diestrus, a sudden fall to a minimum concentration during proestrus and pre-ovulatory estrus, and a progressive increase in concentration during postestrus and diestrus. A parallel is suggested between these modifications and variations in the LH-RH concentration in the median eminence during the estrous cycle.

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confidence: 99%

Immunofluorescence Study of the Preoptico-Infundibular LH-RH Neurosecretory Pathway of the Guinea Pig During the Estrous Cycle

Barry¹,

Dubois²

1974

Neuroendocrinology

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“…Since the chemical structure of hypothalamic LH-RH was determined by Matsuo et al (1971), several LH-RH analogues have been synthesized and their structure-activity-relationships have been discussed (Stievertson et al, 1971;Rivier et al, 1972;Yanaihara et al, 1972;. These synthetic analogues of LH-RH had no or far less activity than natural LH-RH.…”

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confidence: 99%

A New More Potent Analogue of LH-RH

Taya

Igarashi

1974

Endocrinol Japon

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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.…”

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confidence: 97%

“…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.…”

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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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Synthesis of the luteinizing releasing hormone of the hypothalamus and its hormonal activity

Cited by 54 publications

References 13 publications

Immunofluorescence Study of the Preoptico-Infundibular LH-RH Neurosecretory Pathway of the Guinea Pig During the Estrous Cycle

Immunofluorescence Study of the Preoptico-Infundibular LH-RH Neurosecretory Pathway of the Guinea Pig During the Estrous Cycle

A New More Potent Analogue of LH-RH

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

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