title: Synthesis and evaluation of homo-bivalent GnRHR ligands.
abstract: G protein coupled receptors (GPCRs) are important drug targets in pharmaceutical research. Traditionally, most research efforts have been devoted towards the design of small molecule agonists and antagonists. An interesting, yet poorly investigated class of GPCR modulators comprise the bivalent ligands, in which two receptor pharmacophores are incorporated. Here, we set out to develop a general strategy for the synthesis of bivalent compounds that are projected to bind to the human gonadotropin-releasing hormone receptor (GnRHR). Our results on the dimerisation of a known GnRHR antagonist, with as key step the Huisgen 1,3-cycloaddition, and their ability to bind to and antagonize GnRH-induced GnRHR stimulation, are presented here.
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, 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: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Ad P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: Julia
authors.initials: J
authors.lastname: Oosterom
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: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D008024:Ligands; D015394:Molecular Structure; D011966:Receptors, LHRH / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C484844:GNRHR protein, human; D008024:Ligands; D011966:Receptors, LHRH