title: A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor.
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.
authors.affiliation: Wadsworth Center, David Axelrod Institute for Public Health, New York State Department of Health, Albany, NY 12208, United States. JDias@uamail.albany.edu
authors.forename: James A
authors.initials: JA
authors.lastname: Dias
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bonnet
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weaver
authors.forename: Julie
authors.initials: J
authors.lastname: Watts
authors.forename: Kerri
authors.initials: K
authors.lastname: Kluetzman
authors.forename: Richard M
authors.initials: RM
authors.lastname: Thomas
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.forename: Vincent
authors.initials: V
authors.lastname: Mutel
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007457:Iodine Radioisotopes; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011962:Receptors, FSH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects
chemical_list: C000592354:ADX61623; D001549:Benzamides; D007457:Iodine Radioisotopes; D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone