Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT<sub>2A</sub>/mGlu<sub>2</sub> Receptor Complex
作者:Christian B. M. Poulie、Na Liu、Anders A. Jensen、Lennart Bunch
DOI:10.1021/acs.jmedchem.0c01058
日期:2020.9.10
We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu2 receptor complex, based on the 5-HT2A antagonist MDL-100,907 and the mGlu2 ago-PAM JNJ-42491293. The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT2A-, mGlu2/Gqo5-, 5-HT2A/mGlu2-, and 5-HT2A/mGlu2/Gqo5-expressing HEK293 cells using a Ca2+ imaging
我们报告了针对5-HT 2A拮抗剂MDL-100,907和mGlu 2 ago-PAM JNJ-42491293的推定异聚5 -HT 2A / mGlu 2受体复合物的第一系列异二价配体的合成。使用Ca 2在表达5-HT 2A-,mGlu 2 / Gqo5-,5-HT 2A / mGlu 2-和5-HT 2A / mGlu 2 / Gqo5的HEK293细胞中表征一价和异二价配体的功能特性。+成像分析和[ 3H]酮色林结合测定。在5-HT 2A / mGlu 2和5-HT 2A / mGlu 2 / Gqo5细胞中的两个受体之间观察到明显的功能性串扰。虽然合成的一价配体保留了5-HT 2A拮抗剂和mGlu 2 ago-PAM的功能,但七个二价配体抑制了5-HT 2A / mGlu 2细胞中5-HT诱导的应答以及5-HT和Glu诱导的应答5-HT 2A / mGlu 2中的响应/ Gqo5细