Efficacy of Xanomeline in Alzheimer Disease: Cognitive Improvement Measured Using the Computerized Neuropsychological Test Battery (CNTB)

Veroff, Amy E.; Bodick, N.; Offen, Walter W.; Sramek, John J.; Cutler, Neal R.

doi:10.1097/00002093-199812000-00010

Cited by 53 publications

(40 citation statements)

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“…2 The CNTB is a validated measure 4,5 that has been used as a cognitive endpoint for clinical trials. 5,6 CNTB subtests assess motor speed, attention and information processing speed, verbal learning and memory, spatial memory, language, and other spatial functions.…”

Section: Computerized Neuropsychological Test Battery Thementioning

confidence: 99%

“…5,6 The CNTB summary score was chosen as the primary cognitive outcome measure because it has been more extensively validated than subtest measures and has been reported in clinical and observational trials. 4,[6][7][8] Higher scores reflect better performance. CNTB subtest scores were examined in exploratory analyses.…”

Section: Computerized Neuropsychological Test Battery Thementioning

confidence: 99%

See 1 more Smart Citation

Topiramate dose effects on cognition

Loring¹,

Williamson²,

Meador³

et al. 2011

Neurology

104

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Section: Computerized Neuropsychological Test Battery Thementioning

confidence: 99%

Section: Computerized Neuropsychological Test Battery Thementioning

confidence: 99%

Topiramate dose effects on cognition

Loring¹,

Williamson²,

Meador³

et al. 2011

Neurology

104

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show abstract

“…There has been active search for potent muscarinic agonists with selectivity for the M 1 receptor subtype with the aim of pharmacological application of such agonists to compensate for acetylcholine deficiency in Alzheimer's disease because the M 1 receptor is important for learning and memory (McKinney and Coyle, 1991). One of the promising compounds is 3-[3-hexyloxy-1,2,5-thiadiazo-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine (xanomeline) (Bodick et al, 1997;Veroff et al, 1998;Shannon et al, 2000). Xanomeline behaves as an agonist with a high potency, and is functionally selective for the M 1 subtype of muscarinic receptors (Ward et al, 1995;Bymaster et al, 1998;Ward et al, 1998;Wood et al, 1999).…”

mentioning

confidence: 99%

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M₁ Muscarinic Acetylcholine Receptor

Jakubík¹,

Tuček²,

El‐Fakahany³

2002

J Pharmacol Exp Ther

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Xanomeline is a potent agonist that is functionally selective for muscarinic M 1 receptors. We have shown previously that a significant fraction of xanomeline binding to membranes of Chinese hamster ovary (CHO) cells expressing the M 1 receptors occurs in a wash-resistant manner and speculated that this persistent binding likely does not take place at the primary binding site on the receptor. In the present work we investigated in depth the pharmacological characteristics of this unique mode of xanomeline binding and the effects of this binding on the interaction of classical competitive ligands with the receptor in CHO cells that express the M 1 muscarinic receptor. Onset of persistent binding of xanomeline to the M 1 muscarinic receptor was fast and was only slightly hindered by atropine. Its dissociation was extremely slow, with a half-life of over 30 h. Although persistently bound xanomeline strongly inhibited binding of the classical antagonist N-methylscopolamine (NMS) to the receptor, there are multiple indications that this is not the result of competition at the same binding domain. Namely, wash-resistant binding of xanomeline only slightly slowed the rate of NMS association, but enhanced the rate of NMS dissociation. Moreover, preincubation with xanomeline followed by extensive washing brought about an apparent decrease in the number of NMS binding sites. Our findings are best interpreted in terms of allosteric interactions between xanomeline-persistent binding to the M 1 muscarinic receptor and competitive ligands bound to the classical receptor binding site.

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“…Studies investigating the administration of ACh precursors, such as choline, lecithin or ·-glycerylphosphorylcholine have shown minimal efficacy and little or no therapeutic effect [4,28]. The last two strategies, however, have shown some promise, with much attention being paid both to AChE inhibitors [5,29] and to nicotinic and muscarinic agonists [30][31][32].…”

Section: Traditional Pharmacological Approaches To Correcting Cholinementioning

confidence: 99%

Allosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease

Maelicke

2000

Dement Geriatr Cogn Disord

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Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer’s disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common approaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhib- its AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients’ level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine’s modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine’s sustained efficacy.

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Efficacy of Xanomeline in Alzheimer Disease: Cognitive Improvement Measured Using the Computerized Neuropsychological Test Battery (CNTB)

Cited by 53 publications

References 0 publications

Topiramate dose effects on cognition

Topiramate dose effects on cognition

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M₁ Muscarinic Acetylcholine Receptor

Allosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease

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Efficacy of Xanomeline in Alzheimer Disease: Cognitive Improvement Measured Using the Computerized Neuropsychological Test Battery (CNTB)

Cited by 53 publications

References 0 publications

Topiramate dose effects on cognition

Topiramate dose effects on cognition

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M1 Muscarinic Acetylcholine Receptor

Allosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease

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Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M₁ Muscarinic Acetylcholine Receptor