Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2 Receptor Complex

We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu(2) receptor complex, based on the 5-HT2A antagonist MDL100,907 and the mGlu(2) 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/mGlu(2)/Gqo5-expressing HEK293 cells using a Ca2+ imaging assay and a [H-3]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT2A/mGlu(2) and 5-HT2A/mGlu(2)/Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT2A antagonist and mGlu2 agoPAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT2A/mGlu(2) cells and both 5-HT- and Gluinduced responses in 5-HT2A/mGlu2/Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT2A, 5-HT2A/mGlu(2), and 5-HT2A/mGlu(2)/Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex.