A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor.
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) activate the LH receptor/cyclic AMP (cAMP) signaling pathway to induce ovulation. As an alternative to parenterally administered hCG to treat anovulatory infertility, orally active low molecular weight (LMW) LHR agonists have been developed at Organon. In this paper, we present the mechanism of action of a prototypic, nanomolar potent and almost full LHR agonist, Org 43553. Org 43553 interacts with the endodomain of the LHR, whereas LH acts via the N-terminal exodomain. LH stimulates the cAMP pathway with an EC50 of 35 pM, but this stimulation is not antagonized by simultaneous incubation with Org 43553. At nanomolar concentrations, LH also stimulates phospholipase C (PLC), but Org 43553 is hardly able to do so. In contrast, Org 43553 inhibits LH-induced PLC (IC50 approximately 10 nM). While Org 43553 stimulates dissociation of [125I]hCG from the LHR and reduces [125I]hCG binding, LH reduces specific [3H]Org 43553 binding. We conclude that Org 43553 is a signaling-selective, allosteric LHR agonist. We hypothesize that Org 43553 and LH induce a similar LHR conformation necessary for activating adenylyl cyclase, which initiates most, if not all, physiological responses of LH.
Department of Molecular Pharmacology, N.V. Organon, a part of Schering-Plough Corporation, 5340 BH, Oss, The Netherlands. chris.vankoppen@organon.com
Chris J
CJ
van Koppen
Guido J R
GJ
Zaman
C Marco
CM
Timmers
Jan
J
Kelder
Sietse
S
Mosselman
Ruud
R
van de Lagemaat
Martin J
MJ
Smit
Rob G J M
RG
Hanssen
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007986:Luteinizing Hormone / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011974:Receptors, LH / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism
C526583:5-amino-2-methylsulfanyl-4-(3-(2-morpholin-4-ylacetylamino)phenyl)thieno(2,3-d)pyrimidine-6-carboxylic acid tert-butylamide; D006063:Chorionic Gonadotropin; D011743:Pyrimidines; D011974:Receptors, LH; D013876:Thiophenes; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases