Talsaclidine (WAL 2014 FU), a muscarinic M1 receptor agonist for the treatment of Alzheimer's disease

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 beta (Abeta) protein that constitutes the amyloid plaques, one of the neuropathological hallmarks of the disease. In Alzheimer patients, talsaclidine decreased the concentration of Abeta 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.