title: Discovery of selective luteinizing hormone receptor agonists using the bivalent ligand method.
abstract: Two series of dimeric ligands for a G-protein-coupled receptor were prepared that differ by the interconnecting spacer system. Biological evaluation revealed that both dimeric series exhibit unique biological properties relative to their monomeric counterparts.The luteinizing hormone receptor (LHR), the follicle-stimulating hormone receptor (FSHR), and the thyroid-stimulating hormone receptor (TSHR) belong to the glycoprotein hormone receptor (GpHR) family. A prominent feature of all endogenous glycoprotein ligands is that they share an identical alpha subunit and acquire their selectivity from the unique beta subunit. Recent developments in pro-fertility research have led to the discovery of several low-molecular-weight agonists for the luteinizing hormone/choriogonadotropin receptor that bind to the transmembrane (TM) region of the LHR. Interestingly, some of these agonists are also able to activate the FSHR. Several research groups have shown that ligand dimerization presents a powerful tool to increase the subtype selectivity for structurally related G-protein-coupled receptors. In this work, we applied the dimerization strategy to GpHRs and explored the effect on receptors with closely related TM regions. Two series of dimeric ligands were prepared that differ in the interconnecting spacer system. Biological evaluation revealed that both series exhibit unique selectivity properties for the LHR, originating from either decreased potency or a decreased efficacy toward the FSHR.
authors.affiliation: Leiden Institute of Chemistry, Department of Bio-Organic Synthesis, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Bonger
authors.forename: Richard J B H N
authors.initials: RJ
authors.lastname: van den Berg
authors.forename: Annemiek D
authors.initials: AD
authors.lastname: Knijnenburg
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Chris J
authors.initials: CJ
authors.lastname: van Koppen
authors.forename: Cornelis M
authors.initials: CM
authors.lastname: Timmers
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
mesh_terms: D001554:Benzene / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D019855:Ethylene Glycol / Q000737:chemistry; D005640:Follicle Stimulating Hormone / Q000819:agonists / Q000378:metabolism; D008024:Ligands; D011974:Receptors, LH / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011974:Receptors, LH; D011994:Recombinant Proteins; D005640:Follicle Stimulating Hormone; D019855:Ethylene Glycol; D001554:Benzene