Influence of Amine Substituents on 5-HT2A versus 5-HT2C Binding of Phenylalkyl- and Indolylalkylamines
Abstract
The effect of 15 different amine substituents on 5-HT2A and 5-HT2C serotonin receptor binding was investigated for two series of compounds (i.e., phenylalkylamine and indolylalkylamine derivatives). In general, amine substitution decreases receptor affinity; however, N-(4-bromobenzyl) substitution results in compounds that bind at 5-HT2A receptors with high affinity (Ki < 1 nM) and with > 100-fold selectivity. Although parallel structural modification in the two series result in parallel shifts in 5-HT2C binding, these same modifications alter 5-HT2A binding in a less consistent manner.
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This discrepancy reflects the ten-fold better competition of a series of indolylalkylamines such as 5-MeO-DMT against [123I]-DOI-labelled 5HT2A agonist sites as compared to [3H]-ketanserin-labelled 5HT2A antagonist sites.
“This discrepancy doubtless reflects the ten-fold better competition of a series of indolylalkylamines such as 5-MeO-DMT (15) against [123I]-DOI (16)-labelled 5HT2A agonist sites as compared to [3H]-ketanserin-labelled 5HT2A antagonist sites [53].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [53]
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Bufotenine: Toward an understanding of possible psychoactive mechanisms
McBride, M. C. (2000) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2000.10400456 · Cited by 74 · see citing works
Halberstadt, A. L., Nichols, D. E., & Geyer, M. A. (2012) · Psychopharmacology · doi:10.1007/s00213-011-2616-6 · Cited by 57 · see citing works
Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans.
Cumming, P., Scheidegger, M., Dornbierer, D., Palner, M., Quednow, B. B., & Martin-Soelch, C. (2021) · Molecules · doi:10.3390/molecules26092451 · Cited by 43 · see citing works
“This discrepancy doubtless reflects the tenfold better competition of a series of indolylalkylamines such as 5-MeO-DMT (15) against [123I]-DOI (16)-labelled 5HT2A agonist sites as compared to [3H]-ketanserin-labelled 5HT2A antagonist sites [53].”
ResultHarms, A., Gündisch, D., Müller, C. E., & Kovar, K.-A. (2000) · SLAS Discovery · doi:10.1177/108705710000500410 · Cited by 8 · see citing works
- Authors
- Glennon, R. A., Dukat, M., El-Bermawy, M., Law, H., De Los Angeles, J., Teitler, M., King, A., & Herrick-Davis, K.
- Affiliations
- Virginia Commonwealth University (US)
- ORCID
- Glennon, Richard A.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1994-06
- Volume
- 37
- Issue
- 13
- Pages
- 1929-1935
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2013163713
- Cited by
- 67
- References
- 0
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 1 · 2012: 2
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT2A receptor, 5-HT2C receptor, serotonin receptors, amine substituents, phenylalkylamines, receptor binding affinity, receptor selectivity, structure-activity relationship
- MeSH terms
- Binding Sites, Cell Line, Ethylamines, Humans, Indoles, Ketanserin, Phenethylamines, Radioligand Assay, Receptors, Serotonin, Structure-Activity Relationship, Transfection
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