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Hormone Receptor Antagonists (hormone + receptor_antagonist)

Distribution by Scientific Domains

Life Sciences	75%

Selected Abstracts

Synthesis and Pharmacological Evaluation of Dimeric Follicle-Stimulating Hormone Receptor Antagonists

CHEMMEDCHEM, Issue 12 2009
Kimberly
Abstract A series of homo- and heterodimeric compounds encompassing the follicle-stimulating hormone receptor (FSHR) antagonist (R)- 1 and its inactive conformer (S)- 1 connected through ethylene glycol spacers of various lengths is described. Evaluation of these compounds reveals that dimeric compounds, with a spacer of sufficient length, bearing two active copies of the antagonist are more potent relative to dimeric compounds in which one of the active pharmacophores is replaced by an inactive conformer. Interestingly, the opposite trend is observed if a short spacer is used, indicating that these compounds may be valuable tools to study FSHR dimerization in greater detail. [source]

Dynamics of circulating concentrations of gonadotropins and ovarian hormones throughout the menstrual cycle in the bonnet monkey: role of inhibin A in the regulation of follicle-stimulating hormone secretion

AMERICAN JOURNAL OF PRIMATOLOGY, Issue 10 2009
P.S. Suresh
Abstract In higher primates, increased circulating follicle-stimulating hormone (FSH) levels seen during late menstrual cycle and during menstruation has been suggested to be necessary for initiation of follicular growth, recruitment of follicles and eventually culminating in ovulation of a single follicle. With a view to establish the dynamics of circulating FSH secretion with that of inhibin A (INH A) and progesterone (P4) secretions during the menstrual cycle, blood was collected daily from bonnet monkeys beginning day 1 of the menstrual cycle up to 35 days. Serum INH A levels were low during early follicular phase, increased significantly coinciding with the mid cycle luteinizing hormone (LH) surge to reach maximal levels during the mid luteal phase before declining at the late luteal phase, essentially paralleling the pattern of P4 secretion seen throughout the luteal phase. Circulating FSH levels were low during early and mid luteal phases, but progressively increased during the late luteal phase and remained high for few days after the onset of menses. In another experiment, lutectomy performed during the mid luteal phase resulted in significant decrease in INH A concentration within 2,hr (58.3±2 vs. 27.3±3,pg/mL), and a 2- to 3-fold rise in circulating FSH levels by 24,hr (0.20±0.02 vs. 0.53±0.14,ng/mL) that remained high until 48,hr postlutectomy. Systemic administration of Cetrorelix (150,µg/kg body weight), a gonadotropin releasing hormone receptor antagonist, at mid luteal phase in monkeys led to suppression of serum INH A and P4 concentrations 24,hr post treatment, but circulating FSH levels did not change. Administration of exogenous LH, but not FSH, significantly increased INH A concentration. The results taken together suggest a tight coupling between LH and INH A secretion and that INH A is largely responsible for maintenance of low FSH concentration seen during the luteal phase. Am. J. Primatol. 71:817,824, 2009. © 2009 Wiley-Liss, Inc. [source]

Synergistic interaction of endocrine-disrupting chemicals: Model development using an ecdysone receptor antagonist and a hormone synthesis inhibitor

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2004
Xueyan Mu
Abstract Endocrine toxicants can interfere with hormone signaling through various mechanisms. Some of these mechanisms are interrelated in a manner that might result in synergistic interactions. Here we tested the hypothesis that combined exposure to chemicals that inhibit hormone synthesis and that function as hormone receptor antagonists would result in greater-than-additive toxicity. This hypothesis was tested by assessing the effects of the ecdysteroid-synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone on ecdysteroid-regulated development in the crustacean Daphnia magna. Both compounds were individually characterized for effects on the development of isolated embryos. Fenarimol caused late developmental abnormalities, consistent with its effect on offspring-derived ecdysone in the maturing embryo. Testosterone interfered with both early and late development of embryos, consistent with its ability to inhibit ecdysone provided by maternal transfer (responsible for early developmental events) or de novo ecdysone synthesis (responsible for late developmental events). We predicted that, by decreasing endogenous levels of hormone, fenarimol would enhance the likelihood of testosterone binding to and inhibiting the ecdysone receptor. Indeed, fenarimol enhanced the toxicity of testosterone, while testosterone had no effect on the toxicity of fenarimol. Algorithms were developed to predict the toxicity of combinations of these two compounds based on independent joint action (IJA) alone as well as IJA with fenarimol-on-testosterone synergy (IJA+SYN). The IJA+SYN model was highly predictive of the experimentally determined combined effects of the two compounds. These results demonstrate that some endocrine toxicants can synergize, and this synergy can be accurately predicted. [source]

Growth hormone excess and the development of growth hormone receptor antagonists

EXPERIMENTAL PHYSIOLOGY, Issue 11 2008
C. E. Higham
In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH,GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor,GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH,IGF-I axis. [source]