Identification and Characterization of a Selective, Nonpeptide Follicle-Stimulating Hormone Receptor Antagonist

Arey, Brian J.; Deecher, Darlene C.; Shen, Emily S.; Stevis, Panayiotis E.; Meade, Edwin H.; Wrobel, Jay; Frail, Donald E.; López, Francisco J.

doi:10.1210/en.2002-220372

Cited by 56 publications

(63 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Smallmolecule ligands for the subclass of 7TMRs for which the natural ligands are 30-kDa heterodimeric glycoprotein hormones have recently begun to be described, but none have been approved for use in humans. For example, small-molecule agonists (2-5) and an antagonist (6) for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), and small-molecule agonists (7)(8)(9) and antagonists (10)(11)(12) for the FSH receptor (FSHR) have been reported. The thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR) is the third member of the glycoprotein hormone receptor subfamily.…”

mentioning

confidence: 99%

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Neumann¹,

Huang

Titus

et al. 2009

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

113

View full text Add to dashboard Cite

Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.7TMR ͉ G protein-coupled receptor ͉ low-molecular-weight ligands ͉ radioiodide uptake ͉ TSH receptor S mall-molecule agonists and antagonists for 7-transmembrane-spanning receptors (7TMRs; G protein-coupled receptors) make up approximately 40% of the drugs in clinical use (1). The natural ligands for the 7TMRs for which drugs have been discovered are themselves primarily small molecules, such as norepinephrine, adenosine, and acetylcholine. Smallmolecule ligands for the subclass of 7TMRs for which the natural ligands are 30-kDa heterodimeric glycoprotein hormones have recently begun to be described, but none have been approved for use in humans. For example, small-molecule agonists (2-5) and an antagonist (6) for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), and small-molecule agonists (7-9) and antagonists (10-12) for the FSH receptor (FSHR) have been reported. The thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR) is the third member of the glycoprotein hormone receptor subfamily. We recently reported smallmolecule agonists (13) and an antagonist (14) for human TSHR; however, the agonists were of low affinity and were shown to activate TSHRs only in a model cell system in which human TSHRs were ectopically over-expressed.The physiologic role of TSHRs in the hypothalamic-pituitarythyroid axis is well known. TSH, which is produced in the thyrotrophs of the anterior pituitary gland, is secreted into the circulation in response to TSH-releasing hormone stimulation and in turn stimulates the function of the thyroid follicular cells (i.e., thyrocytes) leading, in particular, to increases in size ...

show abstract

mentioning

confidence: 99%

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Neumann¹,

Huang

Titus

et al. 2009

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

113

View full text Add to dashboard Cite

show abstract

“…Much effort has been expended within the pharmaceutical industry in the search for small molecule antagonists of various growth factor receptors with little success, although a small molecule FSH-R antagonist was discovered using a radioligand binding assay (12). However, by screening directly for compounds with agonist activity, small molecule activators have been identified for the insulin receptor (25) and the granulocyte-colony-stimulating factor (G-CSF) receptor (26).…”

Section: Discussionmentioning

confidence: 99%

“…Reporter cell lines expressing each of the chimeric receptors described below were generated in the same manner as for the CHO FSH-R 6XCRE-luciferase cell line. A mouse adrenocortical tumor cell line (Y1 cells) purchased from American Type Culture Collection (Manassas, VA) was engineered to stably express the full-length human FSHR cDNA (provided by Dr. Kerry Koller) as described previously (12).…”

Section: Cell Linesmentioning

confidence: 99%

See 1 more Smart Citation

Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists

Yanofsky

Shen²,

Holden

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC 50's ‫؍‬ 20 M) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC 50 ‫؍‬ 2 nM) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC 50 ‫؍‬ 980 nM) and estradiol production from primary rat ovarian granulosa cells (EC 50 ‫؍‬ 10.5 nM). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy. Follicle-stimulating hormone (FSH)2 is a glycoprotein hormone produced by the anterior pituitary that plays a key role in stimulating ovulation and spermatogenesis. Like other members of the glycoprotein hormone family (luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone (TSH)), FSH is a heterodimeric protein of ϳ30,000 Da that consists of a common ␣-subunit joined noncovalently to a hormone-specific ␤-subunit. FSH activity is mediated through binding to the FSH receptor (FSH-R), which belongs to family I of the large 7-transmembrane-spanning, G protein-coupled receptor (GPCR) superfamily. The glycoprotein hormone receptors are unique among the members of the GPCR family, because they recognize protein hormones and are dominated by a large N-terminal extracellular region (366 amino acids in the case of the FSH-R) that is the predominant site of hormone binding (1, 2) and is required for signal transduction.The binding of FSH to its receptor results in the activation of adenylyl cyclase through heterotrimeric G proteins. Interaction of the activated FSH-R with G s initiates the cAMP signaling cascade (3). The ability of the FSH-R to activate adenylyl cyclase was exploited to generate a Chinese hamster ovary (CHO) FSH-R reporter cell line (4 -6). Screening of a collection...

show abstract

“…В отличие от рецептора ЛГ, в случае рецептора ФСГ синтезированы не только агонисты, но и антагонисты этого рецептора, причем первый из них -производное диазонафталинсульфокислоты -был обнаружен ещё в 2002 г. [38]. Этот антагонист, 7-{4-[бис-(2-карбамоил-этил)-амино]-6-хлор-(1,3,5)-триазин-2-иламино)-4-гидрокси-3-(4-метокси-фенилазо)-нафтален}-2-сульфоновая кислота (вещество 10, рис.…”

Section: рисунок 3 низкомолекулярные агонисты рецептора фолликулостиunclassified

Low-molecular regulators of polypeptide hormones receptors containing LGR-repeats

Шпаков

Shpakova

2010

BIOMED KHIM

View full text Add to dashboard Cite

During the last years the low-molecular non-peptidic regulators of the polypeptide hormones receptors containing LGR-repeats were identified. In the review the data on the structure and the molecular mechanisms of action of these regulators as agonists and antagonists of the luteinizing, follicle-stimulating and thyrotropin hormones are analyzed and systematized. The regulators interact with the serpentine domain of LGR-receptor and trigger the signaling cascades coupled with the receptor. Low-molecular agonists and antagonists of the LGR-receptors are considered as a new generation of the drugs that regulates the functional activity of sensitive to pituitary glycoprotein hormones signaling systems with high efficiency and selectivity. These regulators are more accessible compared to the hormones and can be use orally.

show abstract

Identification and Characterization of a Selective, Nonpeptide Follicle-Stimulating Hormone Receptor Antagonist

Cited by 56 publications

References 33 publications

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists

Low-molecular regulators of polypeptide hormones receptors containing LGR-repeats

Contact Info

Product

Resources

About