Structure–Function Studies of Linear and Cyclized Peptide Antagonists of the GnRH Receptor

Beckers, Thomas; Bernd, Michael; Kutscher, Bernd; Kühne, Ronald; Hoffmann, Silke; Reissmann, Thomas

doi:10.1006/bbrc.2001.5939

Cited by 36 publications

(23 citation statements)

References 48 publications

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“…At 2 h after the start of sampling, ganirelix acetate (GRX) was injected subcutaneously at 0 (saline), 0.1, 0.3, or 1.0 mg/m 2 . GRX is a potent, selective long-acting competitive antagonist of the GnRH receptor (2). GRX, SHBG, and albumin concentrations were measured in a 2-h serum pool (16 -18 h).…”

Section: Methodsmentioning

confidence: 99%

“…According to classical concepts of a competitive ligand-receptor interaction, the magnitude of an observed biological response is determined jointly by concentration(s) of the agonist and any competing antagonist and properties of the receptor-effector response pathway (15). These minimal assumptions are satisfied, because 1) GnRH is the exclusive or predominant physiological agonist of the cognate human pituitary receptor (K d ϭ 0.85 nM) and 2) GRX (Kd ϭ 0.69 nM) acts strictly competitively in vitro and in vivo (2,6,29).…”

Section: Binding Of Te To Carrier Proteinsmentioning

confidence: 99%

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Age-dependent regression analysis of male gonadal axis

Keenan

Veldhuis

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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The mechanisms by which aging progressively depletes testosterone (Te) availability in the male are unknown. Accordingly, the objective was to estimate brain gonadotropin-releasing hormone (GnRH) outflow (release and action), which cannot be observed directly, on the basis of downstream effects on pituitary luteinizing hormone (LH) secretion. LH, in turn, feeds forward on (stimulates) gonadal Te secretion, which then feeds back on (inhibits) GnRH-driven LH secretion. LH and Te concentrations were measured repetitively (every 10 min) over 18 h during graded pharmacological blockade of endogenous GnRH outflow in 24 healthy 20- to 72-yr-old men. Data were analyzed using a new age-dependent regression model of GnRH-LH-Te interactions to estimate pulsatile LH secretion and elimination, GnRH outflow, LH feedforward, and Te feedback. By incorporating regression on age within the dose-response model, we show that aging erodes all three primary forward and reverse pathways linking the brain, pituitary gland, and testes. Aging is associated with concomitant deficits in GnRH --> LH feedforward, LH --> Te feedforward, and Te --> GnRH/LH feedback. The analytical formalism should be generalizable to other ensemble regulatory systems, such as those that control growth, reproduction, stress adaptations, and glucose metabolism.

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Section: Methodsmentioning

confidence: 99%

Section: Binding Of Te To Carrier Proteinsmentioning

confidence: 99%

Age-dependent regression analysis of male gonadal axis

Keenan

Veldhuis

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The -turn conformation appears to be induced in part by the interaction of guanidino group of Arg 8 with an acidic residue (Asp 302 ) in the mammalian receptor. Also, the mutation of Gly 6 by a D-amino acid stabilizes the -turn conformation and improves the binding affinity with the receptor [59,60].…”

Section: Structural Characteristics Of Gnrhmentioning

confidence: 99%

Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Mantzourani¹,

Laimou²,

Matsoukas³

et al. 2008

AIAAMC

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Peptides regulate most physiological processes, mainly by binding to specific receptors located on the cell surface and inducing a series of signals, neurotransmissions or the release of growth factors. There has been a rapid expansion in the use of peptides as therapeutic agents after the 1960s, but a series of unfortunate side effects present in Phase I and II clinical studies combined with their low bioavailability, led to the introduction of the idea of peptidomimetics as alternative compounds that mimic the biological activity of peptides, while offering the advantages of increased bioavailability, biostability, bioefficiency, and bioselectivity. Since then new peptides with promising in vitro results, involving the monoclonal antibody expansion, as well as the newly launched research field for novel formulations for increasing peptides' bioavailability, redirected the interest on the peptide market. In this report we will highlight three areas where the use of peptides has shown promising results, with products that are either currently used as drugs or included into Phase III clinical studies.

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“…Gonadotropin-releasing hormone agonists have affinity coefficients 2 to 50 times higher than that of native GnRH (1). This binding leads to immediate activation of the receptor with all of its respective postreceptor effects; subsequently, internalization and down-regulation ensue.…”

mentioning

confidence: 99%