Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease

Allosteric modulation of AMPA, NR2B, mGlu2, mGlu5 and M1, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Of these targets, clinical promise has been demonstrated using muscarinic activators for the treatment of Alzheimer's disease (AD) and schizophrenia. These diseases have inspired researchers to determine the effects of modulating cholinergic transmission in the forebrain, which is primarily regulated by one of five subtypes of muscarinic acetylcholine receptor (mAChR), a subfamily of G-protein-coupled receptors (GPCRs). Of these five subtypes, M1 is highly expressed in brain regions responsible for learning, cognition and memory. Xanomeline, an orthosteric muscarinic agonist with modest selectivity, was one of the first compounds that displayed improvements in behavioral disturbances in AD patients and efficacy in schizophrenics. Since these initial clinical results, many scientists, including those in our laboratories, have strived to elucidate the role of M1 with compounds that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. A survey of selected compounds in this area will be presented.