Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline

The PET tracer [ 11 C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer’s disease

“…Alternatively, striatal ACh concentrations may be lower in patients, leading to decreased ligand binding affinity. Regardless, if the population of striatal M4R in patients with AD is unchanged relative to healthy participants (10), or if their function is normalized by administration of an AChEI, the ability of these neurons to regulate striatal dopaminergic neurotransmission may continue to be a substrate for modulation by M4 PAMs in the treatment of NPS (9,(34)(35)(36)(37).…”

“…Moreover, the extensive loss of cholinergic pathways (18) and accompanying changes in muscarinic receptor expression reported in AD (19)(20)(21) suggests that patients may not respond to treatment with an M4 PAM if the endogenous agonist or target receptor is no longer present in relevant brain regions. Given that many of the manifestations of NPS resemble an overactivation of dopaminergic pathways (9,22), it is important that the striatal M4R populations regulating dopaminergic neurotransmission remain intact. Currently, there remains uncertainty over the regional status of M4R in brain regions (particularly striatum) of patients with AD, primarily due to a lack of specificity of the orthosteric muscarinic ligands used for both in vitro and in vivo investigations (20,23,24).…”

“…Subsequent investigations support the claim that the clinical effects of xanomeline are mediated primarily by the M4 subtype of muscarinic acetylcholine (ACh) receptors (M4Rs) ( 6 ). M4Rs have long been viewed as a viable therapeutic target for treating schizophrenia and AD ( 6 , 7 ) based on their expression in key brain regions, including the cortex, striatum, and hippocampus ( 8 ), as well as from mechanistic ( 7 , 9 , 10 ) and behavioral studies ( 11 , 12 ). However, targeting the M4R requires high ligand selectivity to avoid the adverse events arising from activation of off-target mAChR subtypes, as observed with xanomeline ( 13 ).…”

The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands

“…M1R and M4R are associated with learning, memory, and cognition 5 , 6 and are promising targets for the treatment of neurological disorders 7 , 8 . For example, xanomeline, a M1R/M4R-preferring agonist, is shown to have positive effects on cognitive and psychotic-like symptoms in Alzheimer’s disease and schizophrenia 9 , 10 . However, clinical development is hindered by the dose-limiting adverse effects of xanomeline, which is due to non-selective activation of other peripheral mAChR subtypes 11 , 12 .…”

Biased Profile of Xanomeline at the Recombinant Human M4 Muscarinic Acetylcholine Receptor

“…Additionally, in a recent study, xanomeline produced M 4 -like effects at significantly lower brain exposures than those at which M 1 -like effects were observed. 22 The M 4 mAChR is known to couple preferentially to the Gα i and Gα o 23 proteins, inhibiting adenylate cyclase (AC). 24,25 However, there is also evidence suggesting that the M 4 mAChR can also couple to Gα s proteins, potentiating AC activity in certain cellular contexts.…”