Pituitary Receptor Site Blockade by a Gonadotropin-Releasing Hormone Antagonist in Vivo: Mechanism of Action

Heber, David; Dodson, Robin E.; Rs, Swerdloff; Channabasavaiah, K.; Jm, Stewart

doi:10.1126/science.6280278

Cited by 91 publications

(38 citation statements)

References 12 publications

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“…Consequently, a significantly faster decrease of the intracellular LH reserves and/or faster exhaustion of the specific release mechanisms occurred, rendering impossible any comparison of the results of the two experimental groups. In our experiments, the average rates of LH release from the cells were similar following 1 (22)(23)(24)(25)(26). Such changes may not occur in isolated membrane preparations widely used for receptor studies, which could result in significant differences between the results of in vivo experiments and data collected by tests on isolated membranes (22)(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 47%

“…In our experiments, the average rates of LH release from the cells were similar following 1 (22)(23)(24)(25)(26). Such changes may not occur in isolated membrane preparations widely used for receptor studies, which could result in significant differences between the results of in vivo experiments and data collected by tests on isolated membranes (22)(23)(24)(25)(26). Since our aim is to elucidate the events that occur in living organisms, we consider the dynamic systems utilizing surviving cells to be promising for testing receptors.…”

Section: Discussionmentioning

confidence: 51%

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Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

Csernus¹

1992

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

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Antagonistic analogues of luteinizing hormone-releasing hormone (LHRH) belong to a class of compounds that can be utilized for treatment of some hormonedependent cancers and gynecologic disorders. Recently, we synthesized and tested a large number of LHRH analogues for LHRH antagonistic activity in the dispersed pituitary cell superfusion system. This fast, reliable, and dynamic system made it possible for us not only to evaluate the relative amounts of an analogue required for suppression of the LH-releasing activity of exogenous LEIRH but also provided quantitative data on dynamic interactions between the LHRH analogue, LHRH receptors, and LH secretion. Three experimental paradigms were used: (i) LHRH responses after preincubation with the antagonist, (ii) pulsatile, simultaneous infusion of LHRH and the antagonistic analogue, and (iW) effects of the analogues on ongoing, continuous LH secretion induced by prolonged stimulation with LHRH. From the data obtained, we conclude that (') the suppression of the LHRH-induced LH release was more effective and longer lasting when the cells were preincubated with the antagonistic analogues before the LBRH stimulation than in the case of simultaneous exposure; (ui) not only the potency but also the time of onset and the duration of the LH release-suppressing activity varied according to the different peptides used, resulting in different shapes of response curves; and (ii) from the accurate data obtained in this dynamic system, quantitative parameters of the in vivo interactions between the antagonists and LBRH on the LHRH receptor can be calculated.In the past few years, a large number of antagonists of luteinizing hormone-releasing hormone (LHRH) has been synthesized and evaluated for therapeutic use (1-6). These analogues may have various practical applications, including treatment of gynecologic disorders and hormone-sensitive tumors such as prostate and breast cancers (1, 2, 7-9). Although chronic administration of LHRH agonists is necessary for inhibition of LH, a single dose of a potent LHRH antagonist is sufficient to evoke the same effect (1, 2, 5-13).

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 51%

Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

Csernus¹

1992

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

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“…The castrated male rat is a sensitive and specific model for evaluating GnRH antagonists (Heber et al, 1982;Puente and Catt, 1986). Removal of the testes produces a model with GnRH-mediated elevations of circulating LH.…”

Section: Discussionmentioning

confidence: 99%

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Anderes¹,

Luthin²,

Castillo³

et al. 2003

J Pharmacol Exp Ther

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Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRHstimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonadintact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [D-Ala 6 , desGly 10 ]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.Gonadotropin-releasing hormone (GnRH) is a neuroendocrine decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-ProGly-NH 2 ) synthesized in the neurovascular terminals of the hypothalamus and is secreted in a pulsatile manner directly into the hypophyseal portal blood supply. GnRH selectively binds specific receptors on the membranes of the anterior pituitary gonadotroph cells to stimulate synthesis and release of the gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)]. LH and FSH stimulate gonadal production of sex steroids and gametogenesis, respectively. GnRH, as the primary regulator of LH, is consequently the primary regulator of the sex hormones testosterone and estrogen. GnRH and its analogs have stimulated much interest because of their potential therapeutic benefit in treating sex hormone-dependent diseases such as prostate, ovarian, and breast cancer, as well as endometriosis, uterine fibroids, benign prostate hyperplasia, fertility disorders, and precocious puberty (Huirne and Lambalk, 2001). In contrast to GnRH agonists, which are associated with an initial surge in LH and testosterone ...

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“…GnRH antagonists competitively block GnRH receptors sites in the anterior pituitary, exerting an immediate inhibitory effect on the gonadal axis (Heber et al, 1982). RS-68439 administartion in male dogs as a single injection @ 100 µg/kg keeps testosterone levels in the castrate range for more than 24 h and its repetitive daily injection results in dry ejaculates after 2 weeks (Vickery, 1985a).…”

Section: Gnrh Antagonistsmentioning

confidence: 99%

Chemical Control of Fertility in Male Dogs: A Review

Soni¹,

Pandey²

2018

Int.J.Curr.Microbiol.App.Sci

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Pituitary Receptor Site Blockade by a Gonadotropin-Releasing Hormone Antagonist in Vivo: Mechanism of Action

Cited by 91 publications

References 12 publications

Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Chemical Control of Fertility in Male Dogs: A Review

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