Of the eight currently identified metabotropic glutamate receptors (mGlu_1-8), mGlu₅ has received recent attention as a promising target for multiple CNS disorders. Several mGlu₅negative allosteric modulators (NAMs) have advanced into clinical trials for several indications, including depression and Fragile X syndrome. In contrast, mGlu₅ positive allosteric modulators (PAMs) may offer a novel approach in the treatment of disorders associated with cognitive dysfunction, e.g. schizophrenia, although their development has proven more challenging due to observed preclinical rodent neurotoxicity. It has since become clear that mGlu₅ ago-PAMs and PAMs with large fold-shifts were responsible for this observed neurotoxicity, and ultimately compounds that display signal bias (e.g. VU0409551) have provided an approach to achieve the benefits of mGlu₅ PAMs without the adverse effect liability. As such, the WCNDD continues to search for new mGlu₅ PAM chemotypes that are devoid of agonism with the potential for signal bias.

In the course of optimizing an M₁PAM chemotype, an unexpected ‘molecular switch’ was discovered to afford a weak, pure mGlu₅ PAM. Herein, we detail efforts towards optimizing this mGlu₅ PAM to deliver a potent, centrally penetrant MPEP-site mGlu₅ PAM (VU6036486) that reversed amphetamine-induced hyperlocomotion. A pronounced ‘magic methyl’ effect was also noted with a regioisomeric methyl congener, leading to a change in pharmacology to afford a potent, centrally penetrant MPEP-site NAM (VU6044766), that displayed anxiolytic activity in a mouse marble burying assay. These data further support the growing body of literature concerning the existence of 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.

Jonathan Dickerson

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