Talsaclidine (WAL 2014 FU), a muscarinic M₁receptor agonist for the treatment of Alzheimer's disease

Abstract

Since the discovery of muscarinic receptor subtypes, extensive research has been going on attempting to provide treatments for diseases related to malfunctions of cholinergic receptors. In Alzheimer's disease, the prevailing symptomatology is a progressive decline in cognitive functions that can be related to a continuing degeneration of cholinergic neurons. Postsynaptic muscarinic M 1 receptors, however, do not decline in number during the course of the disease. Talsaclidine is a functionally selective muscarinic M 1 receptor agonist that has been developed for the symptomatic treatment of Alzheimer's disease. In functional pharmacological assays, talsaclidine was shown to be a full agonist at M 1 receptors while having only partial agonist activities at M 2 -and M 3 receptors. In animal studies, this translated into central cholinergic activation measured in rabbits, cats and rats by EEG recordings, and in an improvement of performance in learning and memory tests in aged animals or in animals with experimentally-induced cholinergic hypofunction. In these studies, cholinergic side effects became apparent in doses higher than those inducing cognitive improvement. In addition to effects increasing cognitive functions, stimulation of M 1 receptors that belong to the class of G protein-coupled, seven transmembrane receptors may have a positive impact on the progression of the disease. Talsaclidine was shown to increase the secretion of the neurotrophic ectodomain of the amyloid precursor protein while simultaneously decreasing the formation of the amyloid b (Ab) protein that constitutes the amyloid plaques, one of the neuropathological hallmarks of the disease. In Alzheimer patients, talsaclidine decreased the concentration of Ab in the cerebrospinal fluid. Despite these encouraging data, talsaclidine failed to improve cognitive symptoms when Alzheimer patients were treated for 3 months. This confirms reports from other muscarinic agonists, none of which has convincingly demonstrated clinical efficacy, and points to the fact that either the pharmacological profile of current M 1 receptor agonists still needs improvement or that muscarinic receptor stimulation alone does not suffice to improve the condition of Alzheimer patients. Drug Dev. Res. 56:321-334, 2002.

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

“…A number of other centrally active muscarinic agonists are reported, including: talsaclidine, 51 YM796, 52 CI-1017, 53 WAY-132983, 54 CS-932, 55 and LY-593093 56 [all claimed to be M1 functionally selective]. A few of the new agonists are defined as allosteric activators of the M1 mAChR.…”

New Trends in the Design of Drugs Against Alzheimer's Disease

“…Although showing promising results (efficacy in models of learning and memory, good pharmacokinetic profile), talsaclidine failed to induce an improvement of cognitive symptoms in AD patients [82].…”

“…It may be conceivable that, to show their full potential, M 1 agonists need to be administrated in combination with other therapeutic agents [82].…”

“…AIT-082 (leteprinim potassium) (82), an analog of hypoxanthine with memory-enhancing property, which is in phase II development and presented as a potential active drug treatment of AD, stroke and motor neuron disease, is also thought to enhance α-secretase activity [98].…”

Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimers Disease

“…Talsaclidine (WAY 2014 FU, 4) is another functionally selective M 1 agonist that has been studied both preclinically and clinically [12]. Talsaclidine shows comparable affinity for the M 1 and M 3 receptors but has 3-4 times less affinity for the M 2 receptor.…”