Identification of a Selective Allosteric Agonist of mGlu

Allosteric modulators for G-protein-coupled receptors (GPCRs) provide numerous advantages over orthosteric ligands, including greater sub-type selectivity, reduced receptor desensitization, saturability of effect, and potential for enhanced therapeutic index. Positive allosteric modulators (PAMs) of the group I metabotropic glutamate receptor mGlu are being pursued as a novel approach to treat all three symptom domains of schizophrenia. Interestingly, we have noted that mGlu PAMs within a single chemotype have the propensity to demonstrate in vitro profiles ranging from pure potentiation, requiring the presence of orthosteric agonist for activation, to robust agonistic activity in the absence of an orthosteric ligand coupled with PAM activity (ago-PAM). Highly selective orthosteric agonists of mGlu are not available; additionally, effective agonists of mGlu with an allosteric mechanism of activation are not known. Herein we describe the SAR and in vitro profile of a series mGlu selective allosteric agonists within an acetylenic picolinamide scaffold. VU0424465 (ML273, SID 125311644/CID 53384845) is the most potent and efficacious ago-PAM within this series and is being declared as a MLPCN probe molecule. ML273 will serve as a significant ago-PAM tool compound for the field with potential for studies within native systems.