The utility of muscarinic agonists in the treatment of alzheimer’s disease

Abstract

Alzheimer's disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer's disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting muscarinic and nicotinic agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of muscarinic agonists. Recent studies suggesting a role for muscarinic agonists in regulating the production of A beta raise the possibility that selective M1 agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer's disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M1 receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M1 agonist with a low side effect profile that enhances memory function in animal models of Alzheimer's disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer's disease.

Allosteric Modulation of M1 Muscarinic Acetylcholine Receptor Internalization and Subcellular Trafficking

“…Radioligand Binding-Cells were plated at 20,000 per well in a 96-well Isoplate (PerkinElmer Life Sciences) and allowed to adhere for at least 16 h. Cells were washed 3 times with binding buffer (146 mM NaCl, 10 mM D-glucose, 5 ELISA-HEK293 cells were transfected with 5 g of c-mychM 1 or empty vector. 24 h post-transfection, cells were plated in poly-D-lysine-coated 48-well culture plates, allowed to adhere, and then grown overnight in serum-free media containing antibiotics.…”

“…The M 1 mAChR couples predominantly to G␣ q/11 G proteins, leading to phospholipase C␤-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate and subsequent calcium mobilization from intracellular stores (3). In the brain the M 1 mAChR is concentrated in forebrain structures such as the frontal cortex and hippocampus, where it is implicated in memory processing and cognition (4), and as such, M 1 mAChRs have been suggested as a target for the development of cognitive enhancers for conditions such as Alzheimer disease (5). Unfortunately, achieving subtype selectivity at mAChRs is challenging given the highly conserved nature of the orthosteric site across the mAChR family.…”

Long-Term Changes in the Muscarinic M1 Receptor Induced by Instantaneous Formation of Wash-Resistant Xanomeline-Receptor Complex

“…Finding a selective M 1 agonist for the treatment of Alzheimer's dementia is necessary to avoid serious side effects, such as salivation and gastrointestinal complications, due to activation of other muscarinic receptor subtypes Messer, 2002). The search for a selective M 1 agonist has been hampered by the highly conserved nature of the orthosteric site among the five receptor subtypes where acetylcholine and other conventional agonists bind (Bonner et al, 1991).…”

Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284

“…Although reported as an M 1 /M 4 mAChR-preferring agonist, xanomeline caused peripherally mediated adverse effects such as nausea, vomiting, salivation, and gastrointestinal distress, which led to a high dropout rate in these dx.doi.org/10.1124/mol.116.104737. ABBREVIATIONS: ACh, acetylcholine; B max , saturable binding capacity; BQCA, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, benzyl quinolone carboxylic acid; CHO, Chinese hamster ovary; CNS, central nervous system; compound 9, 8-((1S,2S)-2-hydroxycyclohexyl)-5-((6-methylpyridin-3-yl)methyl)-8,9-dihydro-7H-pyrrolo [3,4-h]quinolin-7-one; compound 10, (2-((1S,2S)-2-hydroxycyclohexyl)-5-((6-methylpyridin-3-yl)methyl)-1,2-dihydro-3H-benzo[e]isoindol-3-one; compound 12, 5-((6-chloropyridin-3-yl)methyl)-8-((1S,2S)-2-hydroxycyclohexyl)-8,9-dihydro-7H-pyrrolo [3,4-hour]quinolin-7-one; compound 13, 8-((1S,2S)-2-hydroxycyclohexyl)-5-((6-(tributylstannyl)pyridin-3-yl)methyl)-8,9-dihydro-7H-pyrrolo [3,4-hour]quinolin-7-one; DMF, dimethylformamide; FBS, fetal bovine serum; FLIPR, fluorometric imaging plate reader; F u,b , fraction unbound in brain; GPCR, G protein-coupled receptors; hM 1 , human M 1 ; HPLC, high-performance liquid chromatography; [ clinical trials. Alleviating these adverse effects and preserving biologic efficacy by developing subtype-selective orthosteric agonists has proven to be challenging (Messer, 2002) owing to complete homology of the muscarinic receptors at the orthosteric acetylcholine (ACh) site (Kruse et al, 2013).…”