title: Synthesis and evaluation of homodimeric GnRHR antagonists having a rigid bis-propargylated benzene core.
abstract: The fact that GPCRs might function in a dimeric fashion is currently well accepted. For GnRHR, a GPCR that regulates gonadotropin release, there is evidence that the receptor also functions as a dimer. We here describe the design and synthesis of a set of dimeric GnRHR antagonists in order to understand the interaction of dimeric ligands to the receptor and to address the question whether GnRHR dimerization is a prerequisite for signalling. Biological evaluation of the compounds shows no discrimination between monomeric and dimeric-ligands in respect to binding affinities, however, the dimeric ligands appear to have different functional properties.
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: Annemiek D
authors.initials: AD
authors.lastname: Knijnenburg
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: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001554:Benzene / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D030562:Databases, Protein; D019281:Dimerization; D006801:Humans; D007454:Iodides / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D010293:Pargyline / Q000737:chemistry*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D007454:Iodides; D008024:Ligands; D011966:Receptors, LHRH; D010293:Pargyline; D001554:Benzene