Pure Positive Allosteric Modulators (PAMs) of mGlu5 with Competitive MPEP-Site Interaction

A series of acetylenic biaryl mGlu5 positive allosteric modulators (PAMs) have been optimized as pure potentiators in low receptor expressing mGlu5 cell lines. ML254 was identified and shown to competitively interact with the MPEP allosteric binding site. Preliminary data from electrophysiological recordings in native tissues measuring long-term depression (LTD) of transmission at the hippocampal Schaffer collateral synapse (SC-CA1) further establish a pure potentiator mode of action for ML254. ML254 is highly selective for mGlu5 versus other mGlu receptors, has a clean ancillary Ricerca profile, and suitable dystrophia myotonica protein kinase (DMPK) properties for systemic dosing in rodents. Preliminary experiments at a single dose in an in vivo model of psychosis using ML254 demonstrates a robust reversal of amphetamine induced hyperlocomotion. ML254 will serve as a significant pure-PAM tool compound for the field with potential for studies within in vivo paradigms. Structure activity relationship (SAR) and characterization of ML254 are described.