Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGlu2/4 heterodimeric receptor results in a compound with mGlu2/2 homodimer selectivity

This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu(2/4) 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(2/4) heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu(2) PAM at one terminus and an mGlu(4) 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(2) and mGlu(4) but also in cells expressing mGlu(2) or mGlu(4) alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu(2/4) heterodimers; however, another compound displayed 75-fold preference for the mGlu(2/2) homodimer over heterodimeric mGlu(2/4) or homomeric mGlu(4/4). 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.