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Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10201562 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2022.129106 | DOI Listing |
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