Persistent challenges in the development of an mGlu 7 PAM in vivo tool compound: The discovery of VU6046980

Herein, we report on the further chemical optimization of the first reported mGlu positive allosteric modulator (PAM), VU6027459. Replacement of the quinoline core by a cinnoline scaffold increased mGlu PAM potency by ∼ 10-fold, and concomitant introduction of a chiral tricyclic motif led to potent mGlu PAMs with enantioselective mGlu receptor selectivity profiles. Of these, VU6046980 emerged as a putative in vivo tool compound with excellent CNS penetration (K = 4.1; K = 0.7) and efficacy in preclinical models. However, either off-target activity at the sigma-1 receptor or activity at a target not elucidated by large ancillary pharmacology panels led to sedation not driven by activation of mGlu (validated in Grm7 knockout mice). Thus, despite a significant advance, a viable mGlu PAM in vivo tool remains elusive.