Synthesis and evaluation of homodimeric GnRHR antagonists having a rigid bis-propargylated benzene core.
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.
Bonger
Kimberly M
KM
Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
van den Berg
Richard J B H N
RJ
Knijnenburg
Annemiek D
AD
Heitman
Laura H
LH
Ijzerman
Ad P
AP
Oosterom
Julia
J
Timmers
Cornelis M
CM
Overkleeft
Herman S
HS
van der Marel
Gijsbert A
GA
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
D000596:Amino Acids; D007454:Iodides; D008024:Ligands; D011966:Receptors, LHRH; D010293:Pargyline; D001554:Benzene