WAL 2014 FU (talsaclidine): A preferentially neuron activating muscarinic agonist for the treatment of Alzheimer's disease

Abstract

The functional selectivity of WAL 2014 FU with regard to stimulation of the neuronal muscarinic M1 receptor subtype in vitro and in vivo is shown in different receptor preparations, isolated organ models, whole animal testing, and finally humans. From receptor binding experiments in membrane preparations from rat tissues and from Chinese hamster ovary cells expressing human muscarinic receptor subtypes, it can be delineated that the ratio between M1 and M2 (hm1 and hm2) is shifted in favour of the M1 receptor affinity, when compared to several classic muscarinic agonists such as carbachol, arecoline, and oxotremorine. The intermediate GTP‐shift of 7.5 for WAL 2014 FU in a M2 muscarinic receptor preparation (rat heart) indicates only partial agonistic activity at this subtype, carbachol (e.g., shows a shift of 51). Moreover, the ratio from agonist to antagonist receptor binding comparing the affinities using [3H]cis‐methyldioxolane and [3H]N‐methylscopolamine as radioligands, suggests only a partial agonist behaviour at M2 receptors, too. In functional assays in vitro, such as phosphoinositide breakdown measured in cerebral cortex slices from guinea pig brain, WAL 2014 FU is as effective (27.8% compared to carbachol 100%) as arecoline (27.6%), but is more effective than RS 86 (22.1%), oxotremorine (21.6%) or McN‐A‐343 (14.7%). WAL 2014 FU is about as effective as RS 86 and McN‐A‐343 in stimulating the secretion of N‐acetyl‐glucosaminidase from RBL cells transfected with the human m1 receptor subtype. Investigating the proton efflux from CHO cells expressing hm1, hm2, and hm3 muscarinic receptor with cytosensor technology WAL 2014 FU was clearly more effective at human m1 receptors (66.3% compared to carbachol 100%) than at hm3 receptors (18.6%) and showed no measurable effect at hm2 receptor expressing cells. The efficacy in isolated organ preparations and in whole animals has already been reported [Ensinger et al., 1993] and shows the functional selectivity of WAL 2014 FU quite impressively. The general receptor profile of WAL 2014 FU demonstrates a nearly specific interaction with muscarinic receptors, having only weak binding affinity for a1‐ and nicotinic receptors. Results from pharmacokinetic studies in rats and humans indicate high oral bioavailability (>95% in rats) and very low interindividual variation in plasma levels. Furthermore, good penetration of the blood brain barrier with 2.5‐ to 3‐fold higher concentrations of WAL 2014 FU in brain than in plasma could be measured. The advantageous and stable pharmacokinetic profile of WAL 2014 FU and its functional M1 selectivity establish WAL 2014 FU as a promising candidate for drug treatment of Alzheimer's disease. In addition to its role for symptomatic treatment, WAL 2014 FU may also have a disease‐modifying potential because of its stimulatory effects on APPs secretion. Drug Dev. Res. 40:144–157, 1997. © 1997 Wiley‐Liss, Inc.

M1Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M3Receptor Knockout Mice

“…McN-A-343 is an agonist that shows functional selectivity for M 1 receptors (Heldman et al, 1996) but displays nonselective affinity for all muscarinic receptors (Richards and van Giersbergen, 1995;Ensinger et al, 1997). In the present study, McN-A-343 produced a partial agonist relaxant response, with higher concentrations producing a frank contraction in tissues from wild-type mice and a return to baseline force in tissues from M 3 receptor knockout mice.…”

Memory-related task performance by aged rhesus monkeys administered the muscarinic M 1 -preferring agonist, talsaclidine

“…We elected to study the cholinergic M 1 receptorpreferring agonist talsaclidine in aged rhesus monkeys well trained in the performance of a computer-assisted delayed matching-to-sample (DMTS) task. Although talsaclidine binds with comparable affinity to both M 1 and M 2 receptors (Ensinger et al 1993), the drug appears to be functionally selective in vivo at the M 1 receptor (Ensinger et al 1997). Talsaclidine has been evaluated in patients with mild-to-moderate AD and found to produce dose-limiting side effects without convincing improvements in cognitive function (Wienrich et al 2001).…”

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

“…The functional selectivity of talsaclidine at the M 1 -receptor compared to other muscarinic agonists was further confirmed in a functional investigation using the cytosensor technology where muscarinic agonists stimulated proton efflux from CHO cells expressing the human M 1 -, M 2 -, and M 3 -receptor. Talsaclidine stimulated 66.3% of the carbachol-induced proton efflux ( ¼ 100%) in cells expressing the M 1 -receptor; it was inactive at the M 2 -receptor, and only weakly active at the M 3 -receptor (18.6% of the carbachol-induced response) [Ensinger et al, 1997].…”

“…Consequently, medicinal chemistry efforts concentrated on the identification of M 1 -receptor preferring compounds. Interestingly, the classical muscarinic agonists such as carbachol (a stable analogue of acetylcholine), arecoline, or muscarine all have a higher affinity for the M 2 -than for the M 3 -receptor [Ensinger et al, 1997]. In contrast, talsaclidine belongs to a group of compounds with comparable affinity for the M 1receptor in rat hippocampal tissue and the M 2 -receptor in the rat heart (Ki ¼ 6.6 mM in both preparations) and considerable lower affinity for the M 3 -receptor of rat lachrymal glands (Ki ¼ 29.6 mM) [Ensinger et al, 1997].…”

“…Interestingly, the classical muscarinic agonists such as carbachol (a stable analogue of acetylcholine), arecoline, or muscarine all have a higher affinity for the M 2 -than for the M 3 -receptor [Ensinger et al, 1997]. In contrast, talsaclidine belongs to a group of compounds with comparable affinity for the M 1receptor in rat hippocampal tissue and the M 2 -receptor in the rat heart (Ki ¼ 6.6 mM in both preparations) and considerable lower affinity for the M 3 -receptor of rat lachrymal glands (Ki ¼ 29.6 mM) [Ensinger et al, 1997]. In Chinese hamster ovary (CHO) cells transfected with human M 1 -, M 2 -, and M 3 -receptors, talsaclidine preferred the M 2 -over the M 1 -receptor only with a ratio of 3.6 while carbachol clearly expressed preferential binding to the M 2 -receptor (ratio hm1:hm2 ¼ 177, Table 1).…”