Synthesis and evaluation of homo-bivalent GnRHR ligands.
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.
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
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
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
C484844:GNRHR protein, human; D008024:Ligands; D011966:Receptors, LHRH