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

Abstract

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.

FIGURE 1

Representative allosteric modulators of AMPA, NR2B, mGlu₂ and mGlu₅ that address dysfunction in glutamatergic neurotransmission in cortical brain regions.

FIGURE 2

Schematic illustration of the muscarinic acetylcholine receptor subtypes M₁–M₅. The seven transmembrane domains of the family A G-protein-coupled receptors (GPCRs) are highlighted in blue. The orthosteric binding site is indicated in red. A putative allosteric site is illustrated in green and not indicative of a singular or unique site. The downstream effectors indicate M₁ signaling related to the (a) amyloidogenic precursor protein (APP) and subsequent secretase activity to generate soluble amyloidogenic precursor protein alpha (sAPPα), soluble amyloidogenic precursor protein beta (sAPPβ) and Aβ. (b) NMDAR through the CAKβ and SFK pathway. Abbreviations: AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; ERK_1/2, extracellular signal-regulated kinase; IP₃, inositol triphosphate; PKC, protein kinase C; PLC, phospholipase C, CAKβ, cell adhesion kinase β; SFK, Src family kinases.

FIGURE 3

Orthosteric agonists of the M₁ mAChR.

FIGURE 4

M₁ agonists for the treatment of schizophrenia.

FIGURE 5

Nonselective muscarinic antagonists.

FIGURE 6

Brucine, an M₁-selective positive allosteric modulator.

FIGURE 7

Selective allosteric agonists of the M₁ mAChR.

FIGURE 8

M₁-selective allosteric agonists from the Vanderbilt Center for Neuroscience Drug Discovery.

FIGURE 9

M₁-selective positive allosteric modulators from Merck and Vanderbilt Center for Neuroscience Drug Discovery.