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

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The authors discuss targeting allosteric glutamatergic receptors for the possible treatment of cns diseases, in particular schizophrenia

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.

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