WAL 2014 - A muscarinic agonist with preferential neuron-stimulating properties

Ensinger, Helmut A.; Doods, H. N.; Immel-Sehr, A.; Kuhn, F J; Lambrecht, Günter; Mendla, Klaus; Müller, Reinhard; Mutschler, E.; Sagrada, A.; Walther, Guillaume; Hammer, Rudolf

doi:10.1016/0024-3205(93)90304-l

Cited by 47 publications

(22 citation statements)

References 7 publications

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“…Moreover, the compound showed a preference for the M 1 -receptor. In anaesthetized guinea-pigs, the intravenous injection of WAL 2014 FU, in contrast to arecoline, did not cause an increase in airway resistance [3].This discrepancy raised the question of why the muscarinic agonist, WAL 2014 FU, is devoid of bronchospastic activity in vivo. Muscarinic agonists exert bronchospasm by activating M 3 -receptors at the bronchial smooth muscle.…”

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confidence: 87%

“…On the other hand, activation of M 1 -receptors at sympathetic ganglia induces functional antagonism by liberated catecholamines via bronchial β 2 -adrenoceptors. As both compounds induced pressor effects in pithed rats, the bronchospastic effect of arecoline in vivo [3] does not appear to be due to a lack of sympathetic ganglionic activation. It, therefore, seems that the bronchospastic effects of arecoline are more resistant to antagonism by endogenous catecholamines than those of WAL 2014 FU.…”

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confidence: 99%

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“…Cholinergic replacement therapy has been repeatedly attempted with substances exerting muscarinic agonistic actions; however, full exploration of the therapeutic efficacy of this principle has been limited by side-effects [1]. Recently, the muscarinic agonist, WAL 2014 FU, has been introduced as a new candidate for cholinergic replacement therapy, with an action profile in experimental pharmacology that promises less side-effects [3].The existence and physiological importance of muscarinic receptor subtypes is generally recognized and reliable pharmacological methods for drug classification are available [2]. Investigations in isolated tissues characterized WAL 2014 FU as a full muscarinic agonist at M 1 -receptors but as a partial agonist at M 2 -and M 3 -receptors.…”

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Muscarinic contraction in isolated guinea-pig trachea and antagonism by noradrenaline

Walland

Hammer²

1997

Eur Respir J

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In contrast to other muscarinic agonists, WAL 2014 FU does not induce bronchospasm in laboratory animals. The present investigation was intended to test the hypothesis that this is due to a particular susceptibility of the drug's effect to antagonism by catecholamines, as a result of partial M 3 -agonism.The tonic activity of the muscarinic agonists, aceclidine, arecoline, carbachol, McN-A-343, RS 86, thiopilocarpine and WAL 2014 FU, was tested in groups of isolated tracheal muscle of the guinea-pig. Susceptibility to functional antagonism by β-adrenoceptor stimulation was measured by the displacement of the concentration-force curves by 3 µM noradrenaline.Evaluation of the concentration-force relationship revealed differences in potency and intrinsic activity (carbachol=100%) ranging from 114% for arecoline to 36% for thiopilocarpine (WAL 2014 FU=63%). The catecholamine increased the concentration of agonist which induced 5% of the maximum effect achievable Eur Respir J 1997; 10: 1814- Memory impairment in patients with Alzheimer's disease seems to be causally related to the loss of cholinergic neurons in the forebrain. Cholinergic replacement therapy has been repeatedly attempted with substances exerting muscarinic agonistic actions; however, full exploration of the therapeutic efficacy of this principle has been limited by side-effects [1]. Recently, the muscarinic agonist, WAL 2014 FU, has been introduced as a new candidate for cholinergic replacement therapy, with an action profile in experimental pharmacology that promises less side-effects [3].The existence and physiological importance of muscarinic receptor subtypes is generally recognized and reliable pharmacological methods for drug classification are available [2]. Investigations in isolated tissues characterized WAL 2014 FU as a full muscarinic agonist at M 1 -receptors but as a partial agonist at M 2 -and M 3 -receptors. Moreover, the compound showed a preference for the M 1 -receptor. In anaesthetized guinea-pigs, the intravenous injection of WAL 2014 FU, in contrast to arecoline, did not cause an increase in airway resistance [3].This discrepancy raised the question of why the muscarinic agonist, WAL 2014 FU, is devoid of bronchospastic activity in vivo. Muscarinic agonists exert bronchospasm by activating M 3 -receptors at the bronchial smooth muscle. On the other hand, activation of M 1 -receptors at sympathetic ganglia induces functional antagonism by liberated catecholamines via bronchial β 2 -adrenoceptors. As both compounds induced pressor effects in pithed rats, the bronchospastic effect of arecoline in vivo [3] does not appear to be due to a lack of sympathetic ganglionic activation. It, therefore, seems that the bronchospastic effects of arecoline are more resistant to antagonism by endogenous catecholamines than those of WAL 2014 FU.Earlier studies by GRANDORDY et al. [4] and GUNST et al. [5] in isolated bovine and canine tracheal muscle revealed an appreciable receptor reserve for acetylcholine and carbachol but little reserv...

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confidence: 87%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Muscarinic contraction in isolated guinea-pig trachea and antagonism by noradrenaline

Walland

Hammer²

1997

Eur Respir J

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

et al. 1997

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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.

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Cholinergics/Anticholinergics/Muscarinics/Nicotinics

Griffith

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter quickly summarizes the cholinergic nervous system and the structures of muscarinic and nicotinic receptors. The structure–activity relationships of muscarinic agonists and antagonists are discussed with reference to attempts to develop of drugs selective for one of the five muscarinic receptors, both agonist and antagonists. The structure–activity relationships of agonists and antagonists of nicotinic receptors are presented with initial concentration on the neuronal nicotinic receptors and ending with neuromuscular blockers used in surgery.

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WAL 2014 - A muscarinic agonist with preferential neuron-stimulating properties

Cited by 47 publications

References 7 publications

Muscarinic contraction in isolated guinea-pig trachea and antagonism by noradrenaline

Muscarinic contraction in isolated guinea-pig trachea and antagonism by noradrenaline

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

Cholinergics/Anticholinergics/Muscarinics/Nicotinics

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