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Cited by 79Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesNeuroscience and Neuropharmacology Research

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5-HT4 receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: A pharmacodynamic and pharmacokinetic assessment

Shen, Fei, Smith, Jacqueline A.M., Chang, Ray, Bourdet, David L., Tsuruda, Pamela R., Obedencio, Glenmar P., Beattie, David T.·2011·Neuropharmacology
DOI 10.1016/j.neuropharm.2011.02.026
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Abstract

There remains an urgent need for therapeutic agents that provide improved symptomatic treatment and attenuate disease progression in patients with Alzheimer's disease (AD). 5-HT(4) receptors are widely expressed in those CNS areas which receive substantial cholinergic input and are involved in cognition. The ability of 5-HT(4) receptor agonists to increase acetylcholine (ACh) release and reduce cognitive impairment in both animals and humans has been demonstrated. In addition, 5-HT(4) receptor agonist modulation of levels of the amyloid precursor protein (APP) derived peptides, soluble amyloid precursor protein (sAPPα) and amyloid beta protein (Aβ) in the CNS has been reported. In this study, the preclinical properties of three structurally-distinct 5-HT(4) receptor selective agonists, PRX-03140, velusetrag and TD-8954, were studied to assess their potential for symptomatic and disease-modifying benefit in the treatment of AD. All three compounds exhibited high affinity for the rat 5-HT(4) receptor but could be discriminated on the basis of their agonist activity. In cAMP accumulation and sAPPα secretion assays using recombinant HEK293f-5-HT(4(d))-APP(695) cells, velusetrag and TD-8954 were potent, full agonists, relative to 5-HT, whereas PRX-03140 was a partial agonist (intrinsic activity 18%, relative to 5-HT). In a guinea pig colon isolated tissue preparation, TD-8954 exhibited lower intrinsic activity than velusetrag, and PRX-03140 had negligible agonist activity. In the…

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Metadata

Authors
Shen, F., Smith, J. A. M., Chang, R., Bourdet, D. L., Tsuruda, P. R., Obedencio, G. P., & Beattie, D. T.
Affiliations
Theravance Biopharma (United States) (US)
Corresponding author
Shen, Fei
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2011-07
Volume
61
Issue
1-2
Pages
69-79
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2011.02.026
OpenAlex
W2019650137
Cited by
79
References
0
Citations by year
2026: 4 · 2025: 5 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 8 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 12 · 2013: 9 · 2012: 6
FWCI
7.20
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, cognitive enhancement, APP processing, sAPPα, amyloid-beta, cAMP accumulation, scopolamine-induced cognitive deficits, donepezil, acetylcholinesterase inhibitors, CNS penetration, pharmacokinetics
MeSH terms
Animals, Cognition, Dose-Response Relationship, Drug, Guinea Pigs, Humans, Male, Protein Binding, Amyloid beta-Protein Precursor, Rats, Sprague-Dawley, Receptors, Serotonin, 5-HT4, Protein Modification, Translational, Rats, HEK293 Cells, Serotonin 5-HT4 Receptor Agonists

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