Discovery of “Molecular Switches” within a Series of mGlu₅ Allosteric Ligands Driven by a “Magic Methyl” Effect Affording Both PAMs and NAMs with In Vivo Activity, Derived from an M₁ PAM Chemotype

In the course of optimizing an M₁ PAM chemotype, introduction of an ether moiety unexpectedly abolished M₁ PAM activity while engendering a “molecular switch” to afford a weak, pure mGlu₅ PAM. Further optimization was able to deliver a potent (mGlu₅ EC₅₀ = 520 nM, 63% Glu Max), centrally penetrant (K_p = 0.83), MPEP-site binding mGlu₅ PAM 17a (VU6036486) that reversed amphetamine-induced hyperlocomotion. A pronounced “magic methyl” effect was noted with a regioisomeric methyl congener, leading to a change in pharmacology to afford a potent (mGlu₅ IC₅₀ = 110 nM, 3% Glu Min), centrally penetrant (K_p = 0.94), MPEP-site binding NAM 28d (VU6044766) that displayed anxiolytic activity in a mouse marble burying assay. These data further support the growing body of literature concerning the existence of G protein-coupled receptor (GPCR) allosteric privileged structures, and the value and impact of subtle methyl group walks, as well as the highly productive fluorine walk, around allosteric ligand cores to stabilize unique GPCR conformations.