title: Development of Selective LH Receptor Agonists by Heterodimerization with a FSH Receptor Antagonist.
abstract: The structural resemblance of the luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR) impedes selective agonistic targeting of one of those by low molecular weight (LMW) ligands. In the present study, we describe a series of dimeric ligands consisting of a LMW agonist with dual activity on the FSHR and the LHR linked to a selective FSHR antagonist. Biological evaluation shows these compounds to be potent and selective LHR agonists, since no agonistic activity on the FSHR was observed. Equimolar mixing of the monomeric counterparts did not yield the pharmacological profile observed for the heterodimeric ligands, and FSHR agonism of the monomeric LHR agonist was still observed. The here-described results show that ligands with unique pharmacological profiles can be obtained by dimerizing monomeric molecules with distinct apposite properties.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Bonger
authors.affiliation: Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Sascha
authors.initials: S
authors.lastname: Hoogendoorn
authors.affiliation: Department of Molecular Pharmacology and MDPK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: van Koppen
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: C Marco
authors.initials: CM
authors.lastname: Timmers
authors.affiliation: Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.affiliation: Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
keywords: G-protein-coupled receptor; Luteinizing hormone receptor; bivalency; dimeric ligands; follicle-stimulating hormone receptor