Identification of a high affinity MPEP-site silent allosteric modulator (SAM) for the metabotropic glutamate subtype 5 receptor (mGlu5)

Allosteric modulators of the group I metabotropic glutamate receptor mGlu₅ can span positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), allosteric agonists (ago-PAMs), and the rarer neutral or silent allosteric modulators (SAMs). Within this latter category of allosteric ligands, SAMs bind to the receptor at an allosteric site but lack cooperativity for calcium mobilization via the Gq-PLC-IP₃ pathway. However, it is conceivable that a SAM may modulate other aspects of receptor function at pathways independent of calcium mobilization. This phenomenon is more generally referred to as stimulus or signaling bias. Understanding the nature and existence of such signaling profiles with SAMs could be valuable in the identification of allosteric ligands as central nervous system (CNS) therapeutics, and may offer an approach to develop ligands with enhanced therapeutic index. To date, two classes of SAMs have been partially characterized for their basic molecular pharmacology and these include the MPEP-site silent ligand, 5MPEP, and VU0365396, a benzamide based silent modulator, thought to interact at a distinct site outside the MPEP-site. In the case of 5MPEP, a Ki of 388 nM was reported using the MPEP-site radioligand [3H]-methoxyPEPy. We describe the structure activity relationship (SAR) and in vitro profile of a novel picolinamide acetylene class of mGlu₅ SAMs leading to MLPCN probe molecule ML353 (VU0478006, SID 160963303/CID 70789094), an mGlu₅ SAM selective ligand with a >20-fold improvement in affinity at the common allosteric site.