ArticleMolecular and cellular endocrinology2011
A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor.
Article in Molecular and cellular endocrinology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 53 citations in OpenAlex.
- Allosteric modulation of gonadotropin receptors.Frontiers in endocrinology · 2023Review
- Pharmacological Characterization of Low Molecular Weight Biased Agonists at the Follicle Stimulating Hormone Receptor.International journal of molecular sciences · 2021Article
- Recent advances in understanding gonadotropin signaling.Faculty reviews · 2021Review
- FSH-R Human Early Male Genital Tract, Testicular Tumors and Sperm: Its Involvement in Testicular Disorders.Life (Basel, Switzerland) · 2020Article
- Follicle-stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles.Journal of clinical medicine · 2020Review
- FSH for the Treatment of Male Infertility.International journal of molecular sciences · 2020Review
- Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor.Frontiers in pharmacology · 2020Article
- Follicle-Stimulating Hormone Glycobiology.Endocrinology · 2019Review
- Biased Signaling and Allosteric Modulation at the FSHR.Frontiers in endocrinology · 2019Review
- FSHR Trans-Activation and Oligomerization.Frontiers in endocrinology · 2018Review
- Review
- Small Molecule Follicle-Stimulating Hormone Receptor Agonists and Antagonists.Frontiers in endocrinology · 2018Review
- In Vitro Effects of the Endocrine Disruptor p,p'-DDT on Human Follitropin Receptor.Environmental health perspectives · 2016Article
- Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.Chemical reviews · 2016Review
- An Investigation on a Novel Anti-tumor Fusion Peptide of FSH33-53-IIKK.Journal of Cancer · 2016Article
- Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism.Neuropharmacology · 2015Article
- Discovery and Development of Small Molecule Allosteric Modulators of Glycoprotein Hormone Receptors.Frontiers in endocrinology · 2015Review
- Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer.The Journal of biological chemistry · 2014Article
- Inhibition of follicle-stimulating hormone-induced preovulatory follicles in rats treated with a nonsteroidal negative allosteric modulator of follicle-stimulating hormone receptor.Biology of reproduction · 2014Article
- The follicle-stimulating hormone receptor: a novel target in genitourinary malignancies.Urologic oncology · 2013Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
High quality gamete production in males and females requires the pituitary gonadotropin follicle stimulating hormone (FSH). In this report a novel chemical class of small molecule inhibitors of FSH receptor (FSHR) is described. ADX61623, a negative allosteric modulator (NAM), increased the affinity of interaction between (125)I-hFSH and human FSHR (hFSHR) five fold. This form of FSHR occupied simultaneously by FSH and ADX61623 was inactive for cAMP and progesterone production in primary cultures of rat granulosa cells. In contrast, ADX61623 did not block estrogen production. This demonstrates for the first time, biased antagonism at the FSHR. To determine if ADX61623 blocked FSH induction of follicle development in vivo, a bioassay to measure follicular development and oocyte production in immature female rats was validated. ADX61623 was not completely effective in blocking FSH induced follicular development in vivo at doses up to 100mg/kg as oocyte production and ovarian weight gain were only moderately reduced. These data illustrate that FSHR couples to multiple signaling pathways in vivo. Suppression of one pool of FSHR uncouples Gαs and cAMP production, and decreases progesterone production. Occupancy of another pool of FSHR sensitizes granulosa cells to FSH induced estradiol production. Therefore, ADX61623 is a useful tool to investigate further the mechanism of the FSHR signaling dichotomy. This may lead to a greater understanding of the signaling infrastructure which enables estrogen biosynthesis and may prove useful in treating estrogen dependent disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.