Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens.
R A Lyon, M Titeler, M R Seggel, Richard A Glennon
European Journal of Pharmacology 1988 DOI: 10.1016/0014-2999(88)90432-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro radioligand binding study Peer reviewed |
|---|---|
| Population | Rat brain cortical 5-HT2 receptors |
| Measures | [3H]ketanserin binding, [3H]DOB binding |
| Topics | Serotonin |
| Keywords | Cerebral cortex Animals Rats, inbred strains Amines Ketanserin Indoles Receptors, serotonin Serotonin antagonists Hallucinogens Radioligand assay Structure-activity relationship Methylation Computer simulation In vitro techniques Dom 2,5-dimethoxy-4-methylamphetamine |
| Key points | Binding affinity of indolealkylamines at rat cortical 5-HT2 receptors depends on aromatic substituent position: 4- or 5-methoxy substitution confers higher affinity than 6- or 7-methoxy; a 7-hydroxyl group essentially abolishes affinity while 7-methyl or 7-bromo enhances it. Terminal amine methylation produces a small progressive decrease in affinity (primary > dimethyl > diethyl), and alpha-methylation has little effect. Selected compounds fit a two-site model better than a one-site model, and affinities measured with the agonist radioligand [3H]DOB were 10-100-fold higher than with [3H]ketanserin. |
Abstract
Twenty-one indolealkylamines, some of which are known to be psychoactive in man, were examined for their binding interactions with rat brain cortical 5-HT2 receptors labeled with the antagonist radioligand [3H]ketanserin in order to develop structure-activity relationships for binding at these sites. Features investigated included aromatic, alpha-methyl and terminal amine substituents. 4-Methoxy and 5-methoxy substitution impart a higher affinity than 6- or 7-methoxy substitution; a 7-hydroxyl group essentially abolishes affinity whereas a 7-methyl or 7-bromo group enhances affinity. alpha-Methylation has little effect on affinity and, in the one case examined, the S(+) isomer of alpha-methyltryptamine was essentially equipotent with its racemate and twice as potent as its R(-) enantiomer. Terminal amine methylation results in a small but progressive decrease in affinity in the order: primary amine greater than dimethylamine greater than diethylamine. Similarities were noted between these structural requirements for binding and those of the phenalkylamines. Selected compounds (5-methoxytryptamine, N,N-dimethyltryptamine, 5-methoxy-N,N-diethyltryptamine and 5-methoxy-N,N-dimethyltryptamine) were further examined by two-site analysis of displacement studies for [3H]ketanserin specific binding. Hill coefficients were significantly less than unity and computer-assisted analysis indicated that a two-site model better fit the data than a one-site model. In displacement studies using the putative agonist radioligand [3H]DOB to label 5-HT2 receptors affinities were 10-100-fold higher than those using [3H]ketanserin. These results are also consistent with earlier findings using psychoactive phenalkylamines in competition studies for radiolabelled 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparable studies
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| Study | Year | Design | Participants |
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| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 31
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- Neuropharmacology of N,N-dimethyltryptamine Brain Research Bulletin April 30, 2016
- Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Pharmacology, Biochemistry, and Behavior 2006
- Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Journal of Medicinal Chemistry 1996
- Investigation of the Structure–Activity Relationships of Psilocybin Analogues ACS Pharmacology & Translational Science December 14, 2020
and 26 more in the library
Cites 3
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) labels a guanyl nucleotide-sensitive state of cortical 5-HT2 receptors. Molecular Pharmacology February 1, 1987
- Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists. Brain Research October 1, 1986