Syntheses and biological activities of analogs of luteinizing hormone releasing hormone (LH-RH)

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

doi:10.1016/0006-291x(72)90467-6

Cited by 47 publications

(8 citation statements)

References 15 publications

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“…There is the possibility, therefore, that the antisera could cross-react and inhibit an FSH-RH if it had an amino acid sequence identical with that of the C02H-terminus of LH-RH but different to the NH2-terminus. This has been shown to be unlikely, as a wide variety of LH-RH fragments have been tested and shown to possess little or no FSH releasing activity (Fujino, Kobayashi, Obayashi, Fukuda, Shinagawa, Yamazaki & Nakayama, 1972;Monahan, Rivier, Vale, Guillemin & Burgus, 1972;Schally, Arimura, Carter, Redding, Geiger, König, Wissman, Jaeger, Sandow, Yanaihara, Yanaihara, Hashimoto & Sakagami, 1972;Okada, Kitamura, Baba, Arimura & Schally, 1973;Yanaihara, Tsuji, Yanaihara, Hashimoto, Kaneko, Oka, Arimura & Schally, 1973). Also, Jeffcoate, Sharp, Fraser, Holland & Gunn (1974) have shown, using ion-exchange chromatography on carboxymethylcellulose, that there is a single immunoreactive substance with the mobility of the decapeptide in rat hypo¬ thalamic extracts.…”

Section: Resultsmentioning

confidence: 93%

Effect of Active Immunization to Luteinizing Hormone Releasing Hormone on Serum and Pituitary Gonadotrophins, Testes and Accessory Sex Organs in the Male Rat

Fraser¹,

Gunn²,

Jeffcoate³

et al. 1974

Journal of Endocrinology

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Autoimmunity to luteinizing hormone releasing hormone (LH-RH) in adult male rats, induced by immunization with LH-RH conjugated to bovine serum albumin, resulted in atrophy of the testes and secondary sex organs and aspermatogenesis. Both immunoreactive luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum and the pituitary were reduced to low levels compared with those of control animals. It is suggested that antibodies to LH-RH can inhibit the action of endogenous hormone and that LH-RH is, in fact, the gonadotrophin-releasing hormone in the rat, required for the release of both LH and FSH.

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Section: Resultsmentioning

confidence: 93%

Effect of Active Immunization to Luteinizing Hormone Releasing Hormone on Serum and Pituitary Gonadotrophins, Testes and Accessory Sex Organs in the Male Rat

Fraser¹,

Gunn²,

Jeffcoate³

et al. 1974

Journal of Endocrinology

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“…The product was eluted with CHCL-EtOH' (19:1): yield, 20 mg. (GnRH),1'6 as well as of GnRH analogs.7 '13 In a collaborative project with Takeda Industries, Ltd., the effects of simple substitution of several of the amino acids in the GnRH molecule with other naturally occurring amino acids have been studied. 12 In a recent report the effect of modification of an amide function on proline in position 9 has been explored. From these efforts have emerged several noteworthy agonists in the [des-Gly10] series,13 one of which demonstrates up to five times the activity of GnRH.…”

mentioning

confidence: 99%

Synthesis and biological activity of some analogs of the gonadotropin releasing hormone

Arnold¹,

Flouret²,

Morgan³

et al. 1974

J. Med. Chem.

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“…Numerous peptide GnRH derivatives have been synthesized and studied for their so‐called structure–affinity relationships, with the aim to improve their affinity, potency and/or metabolic stability (Fujino et al ., ; Monahan et al ., ; Karten and Rivier, ; Sealfon et al ., ; Hovelmann et al ., ; Millar et al ., ) In summary, it was established that the NH 2 ‐terminal domain (pGlu–His–Trp–Ser) of GnRH is important for receptor binding and activation with Trp 3 as a critical residue. In addition, the COOH‐terminal domain (Pro–Gly–NH 2 ) is crucial for receptor binding where substitution of Pro 9 or removal of NH 2 results in very low affinity unless the COOH‐terminal tail is substituted for an ethylamide, which also improves metabolic stability.…”

Section: Discussionmentioning

confidence: 99%

Characterization of 12 GnRH peptide agonists – a kinetic perspective

Nederpelt

Georgi

Schiele

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEDrug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor-binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor-binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. EXPERIMENTAL APPROACHA novel radioligand-binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [ 125 I]-triptorelin. In addition to radioligand-binding studies, a homogeneous time-resolved FRET Tag-lite ™ method was developed as an alternative assay for the same purpose. KEY RESULTSTwo novel competition association assays were successfully developed and applied to determine the kinetic receptor-binding characteristics of 12 high-affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). CONCLUSIONS AND IMPLICATIONSOur research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. AbbreviationsCHOhGnRH, CHO cells stably expressing the human GnRH receptor; GnRH, gonadotropin-releasing hormone; k 1 , the association rate constant of the radioligand; k 2 , the dissociation rate constant of the radioligand; k 3 , the association rate constant of the unlabelled ligand; k 4 , the dissociation rate constant of the unlabelled ligand; RT, residence time; TR-FRET, time-resolved FRET

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Syntheses and biological activities of analogs of luteinizing hormone releasing hormone (LH-RH)

Cited by 47 publications

References 15 publications

Effect of Active Immunization to Luteinizing Hormone Releasing Hormone on Serum and Pituitary Gonadotrophins, Testes and Accessory Sex Organs in the Male Rat

Effect of Active Immunization to Luteinizing Hormone Releasing Hormone on Serum and Pituitary Gonadotrophins, Testes and Accessory Sex Organs in the Male Rat

Synthesis and biological activity of some analogs of the gonadotropin releasing hormone

Characterization of 12 GnRH peptide agonists – a kinetic perspective

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