Pharmacological characterization of two novel and potent 5‐HT4receptor agonists, RS 67333 and RS 67506,in vitro and in vivo
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1. The pharmacology of two novel 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxy-phenyl)-3-[1(n-butyl)-4-piperidinyl]-1- propanone HCl) and RS 67506 (1-(4-amino-5-chloro-2-methoxy-phenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone HCl) have been assessed in vitro and in vivo. 2. RS 67333 and RS 67506 exhibited affinities (pKi = 8.7 and 8.8, respectively) for the 5-HT4 binding sites, labelled with [3H]-GR 113808, in guinea-pig striatum. The Hill coefficients from these displacement curves were not significantly different from unity. The compounds exhibited lower affinities (< 6.0) at several other receptors including 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C, dopamine D1, D2 and muscarinic M1-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the sigma 1 (pKi = 8.9 and 7.9, respectively) and sigma 2 (pKi = 8.0 and 7.3, respectively) binding sites. 3. At the 5-HT4 receptor mediating relaxation of the carbachol-precontracted oesophagus, RS 67333 and RS 67506 acted as potent (pEC50 8.4 and 8.6, respectively), partial agonists (intrinsic activities, with respect to 5-HT were 0.5 and 0.6, respectively) with respect to 5-HT. Relaxant responses to RS 67333 or RS 67506 were surmountably antagonized by GR 11308 (10 nM), with apparent affinities (pKB) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose-dependent increases in heart rate of the anaesthetized micropig (ED50 4.9 and 5.4 micrograms kg-1, i.v.), with maximal increases of 35 and 47 beats min-1, respectively. 4. RS 67333 and RS 67506, therefore, acted as potent, partial 5-HT4 receptor agonists in vitro and in vivo. These compounds, by virtue of their high potency and selectivity, may have some utility in elucidating the physiological role of 5-HT4 receptors.
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Co-administration of RS67333 (26) at 0.1 mg/kg and donepezil (1) at 0.3 mg/kg at subactive doses resulted in improved memory performances in mice.
“In this case, 26 (0.1 mg/kg) and 1 (0.3 mg/kg), when co-administrated at subactive doses, resulted in improved memory performances in mice.”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [107]
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- Authors
- Eglen, R. M., Bonhaus, D. W., Johnson, L. G., Leung, E., & Clark, R. D.
- Corresponding author
- Eglen, R.M.
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 1995-08
- Volume
- 115
- Issue
- 8
- Pages
- 1387-1392
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC1908873
- OpenAlex
- W1982211349
- Cited by
- 102
- References
- 26
- Citations by year
- 2026: 4 · 2025: 2 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 2 · 2016: 2 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 4
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- 5-HT4 receptor agonist, serotonin receptors, sigma receptors, receptor binding affinity, heart rate, blood pressure, partial agonists, anticholinergic activity, antihistaminic activity
- MeSH terms
- Animals, Binding, Competitive, Carbachol, Corpus Striatum, Esophagus, Guinea Pigs, Heart Rate, Muscle, Smooth, Receptors, Muscarinic, Receptors, Serotonin, Swine, Swine, Miniature, Serotonin Receptor Agonists, Receptors, Dopamine D1, Receptors, Dopamine D2, Receptors, Serotonin, 5-HT4, Rats, In Vitro Techniques
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