Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGlu heterodimeric receptor results in a compound with mGlu homodimer selectivity.

This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu PAM at one terminus and an mGlu PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu and mGlu but also in cells expressing mGlu or mGlu alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu heterodimers; however, another compound displayed 75-fold preference for the mGlu homodimer over heterodimeric mGlu or homomeric mGlu. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs.