Bonger Kimberly M, van den Berg Richard J B H N, Heitman Laura H, IJzerman Ad P, Oosterom Julia, Timmers Cornelis M, Overkleeft Herman S, van der Marel Gijsbert A
Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Bioorg Med Chem. 2007 Jul 15;15(14):4841-56. doi: 10.1016/j.bmc.2007.04.065. Epub 2007 May 6.
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.
G蛋白偶联受体（GPCRs）是药物研究中的重要药物靶点。传统上，大多数研究工作都致力于小分子激动剂和拮抗剂的设计。一类有趣但研究较少的GPCR调节剂包括二价配体，其中包含两个受体药效基团。在这里，我们着手开发一种合成预计与人促性腺激素释放激素受体（GnRHR）结合的二价化合物的通用策略。本文展示了我们关于一种已知GnRHR拮抗剂二聚化的研究结果，其关键步骤是Huisgen 1,3-环加成反应，以及它们结合并拮抗GnRH诱导的GnRHR刺激的能力。
