4‐Aryl‐Substituted 2,5‐Dimethoxyphenethylamines: Synthesis and Serotonin 5‐HT2AReceptor Affinities
Daniel Trachsel, David E. Nichols, Stephanie Kidd, Marcel Hadorn, Franz Baumberger
Chemistry & Biodiversity May 1, 2009 DOI: 10.1002/cbdv.200800235 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Moiety Pharmacophore Aryl Substituent Stereochemistry Biphenyl 5-HT Receptor Binding affinities Phenethylamines Organic chemistry Alkyl Biochemistry |
| Citations | 15 |
| Key points | Most novel 4'-aryl-substituted 2-phenylethylamines are antagonists with low affinity at the rat 5-HT(2A) receptor, except for 4''-butyl, 4''-phenyl, and 4'-naphthyl derivatives which show relatively high affinity. |
Abstract
A series of novel ligands for the serotonin 5-HT(2A/C) receptor subtype bearing the 2-phenylethylamine pharmacophore was synthesized and assayed for its 5-HT(2A) receptor binding affinity. As the 4'-aryl-substituted 2-(2,5-dimethoxyphenyl)ethylamines were previously unknown, an initial series of twelve compounds was chosen to obtain initial insight into their structure-activity relationships. The 4'-aryl moiety was introduced in moderate-to-high yield by a Pd-catalyzed Suzuki reaction of twelve arylboronic acids with N-Boc-protected 2-(2,5-dimethoxy-4-iodophenyl)ethylamine (8). N-Boc Deprotection then afforded the novel 2-phenylethylamines 5a-5l. Additionally, biphenyl compound 6 lacking the 5'-MeO substituent was prepared, starting from 2-methoxy-4-hydroxybenzaldehyde. Except for 5l, all of the compounds proved to be antagonists with generally low affinity at the rat 5-HT(2A) receptor. Substituents are generally not well tolerated on the 4'-aryl moiety, except in the 4''-position. Indeed, the relatively high affinity of the 4''-butyl-, 4''-phenyl-, and 4'-naphthyl-substituted compounds 5i, 5k, and 5e, respectively (K(i)=32, 33, and 41nM, resp.), attests a rather remarkable tolerance for bulk in this location.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 7
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
- Monoamine receptor interaction profiles of 4-aryl-substituted 2,5-dimethoxyphenethylamines (2C-BI derivatives). European Journal of Pharmacology July 1, 2019
- Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines Frontiers in Pharmacology February 9, 2022
- Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq. Journal of Medicinal Chemistry June 18, 2025
- Receptor interaction profiles of 4-alkoxy-2,6-dimethoxyphenethylamines (Ψ derivatives) and related amphetamines Frontiers in Pharmacology November 20, 2025
and 2 more in the library
Cites 8
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- [125I]-2-(2,5-dimethoxy-4-iodophenyl)aminoethane ([125I]-2C-I) as a label for the 5-HT2 receptor in rat frontal cortex. Pharmacology, Biochemistry, and Behavior 1990
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and 3 more in the library