title: Signaling of an allosteric, nanomolar potent, low molecular weight agonist for the follicle-stimulating hormone receptor.
abstract: Follicle-stimulating hormone (FSH) activates FSH receptors (FSHR) in granulosa cells to induce follicle differentiation, growth and estradiol production. FSH is used clinically to treat female infertility and is administered by injection. To increase patient convenience and compliance, compound homogeneity and composition, low molecular weight (LMW), orally bioavailable, FSHR agonists are now being developed to replace FSH. In this study, we present the signaling mechanisms of a newly developed LMW dihydropyridine agonist of the FSHR, Org 214444-0. Org 214444-0 is shown to be a stereoselective, nanomolar potent FSHR agonist and selective over the structurally related LHR and TSHR. Org 214444-0 is an allosteric agonist interacting with the transmembrane region of the FSHR. When co-incubated with FSH, Org 214444-0 augments FSH's potency in binding (6.5-fold) and adenylyl cyclase/cAMP activation (3.5-fold) in a concentration-dependent manner. Like FSH, Org 214444-0 induces FSHR internalization and is only marginally effective in stimulating phospholipase C. Moreover, Org 214444-0 stimulates cAMP and estradiol production in human granulosa cells in culture and supports the follicular phase in mature female rats. We conclude that Org 214444-0 is a bonafide FSHR agonist.
authors: Departments of Molecular Pharmacology & DMPK, Merck Research Laboratories, MSD, Oss, The Netherlands. chris.vankoppen@online.de
authors: Chris J
authors: CJ
authors: van Koppen
authors: Pieter M
authors: PM
authors: Verbost
authors: Ruud
authors: R
authors: van de Lagemaat
authors: Willem-Jan F
authors: WJ
authors: Karstens
authors: Huub J J
authors: HJ
authors: Loozen
authors: Tanja A E
authors: TA
authors: van Achterberg
authors: Monique G A
authors: MG
authors: van Amstel
authors: Jolanda H G M
authors: JH
authors: Brands
authors: Els J P
authors: EJ
authors: van Doornmalen
authors: Jesse
authors: J
authors: Wat
authors: Saskia J
authors: SJ
authors: Mulder
authors: Bianca C
authors: BC
authors: Raafs
authors: Saskia
authors: S
authors: Verkaik
authors: Rob G J M
authors: RG
authors: Hanssen
authors: C Marco
authors: CM
authors: Timmers
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D051381:Rats; D011962:Receptors, FSH / Q000819:agonists* / Q000737:chemistry; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D004095:Dihydropyridines; C581097:N-(2-(2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxyphenoxymethyl)-4,5-difluorophenyl)methanesulfonamide; D011962:Receptors, FSH; D013449:Sulfonamides; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D010738:Type C Phospholipases