Serotonin autoreceptors on dorsal raphe neurons: structure-activity relationships of tryptamine analogs
MA Rogawaski, George K. Aghajanian
Journal of Neuroscience October 1, 1981 DOI: 10.1523/jneurosci.01-10-01148.1981 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacology study Peer reviewed |
|---|---|
| Population | Single dorsal raphe serotonergic neurons in rats |
| Interventions | N 5-methoxy-N N-dimethyltryptamine |
| Topics | Serotonin |
| Citations | 52 |
| Key points | The serotonin autoreceptor ("S2 receptor") mediating inhibition of raphe serotonergic neurons exhibits high structural specificity among tryptamine analogs. Activity follows the ring-position order 5 much greater than 4 greater than 6; methoxy derivatives are more sensitive to substituent shifts than hydroxy compounds; N,N-dimethylation enhances activity; and 7-methylation of 5-methoxy-N,N-dimethyltryptamine markedly reduces agonist activity. D-[3H]lysergic acid diethylamide binding best corresponds to the S2 receptor profile, though a complete comparison awaits further data. |
Abstract
A series of indole-ethylamines were tested for their ability to suppress the spontaneous firing of single dorsal raphe serotonergic neurons in the rat. The compounds were all derivatives of either tryptamine or N,N-dimethyltryptamine possessing hydroxy or methoxy substituents on the benzene ring portion of the indole nucleus. Their activity was assessed using quantitative microiontophoresis or following systemic (intravenous) administration. The serotonin autoreceptor or so-called "S2 receptor" mediating the inhibition of raphe serotonergic neurons was found to exhibit a high degree of structural specificity among the closely related tryptamine analogs. The following structure-activity rules were demonstrated: (1) for either hydroxy or methoxy derivatives, the relative favorability of the ring positions conforms to the series 5 much greater than 4 greater than 6; (2) methoxy derivatives are more sensitive to a shift of the ring substituent from the 5- to the 4- or 6-positions than are hydroxy compounds; and (3) activity is enhanced by N,N-dimethylation. Furthermore, addition of a methyl group at the 7-position of 5-methoxy-N,N-dimethyltryptamine markedly reduces the activity of this potent agonist. Of the radioligands which label brain serotonin receptors, the pharmacological characteristics of D-[3H]lysergic acid diethylamide binding best correspond to those displayed by the S2 receptor as determined in the present physiological analysis, although sufficient data are not yet available to make a complete comparison.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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 11
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- The hallucinogenic world of tryptamines: an updated review. Archives of Toxicology August 1, 2015
- Clinical toxicology of newer recreational drugs Clinical Toxicology October 1, 2011
- The recreational tryptamine 5-MeO-DALT (N,N-diallyl-5-methoxytryptamine): a brief review. Progress in Neuro-Psychopharmacology and Biological Psychiatry December 3, 2012
- Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy-N,N-dimethyltryptamine. Brain research. Developmental brain research June 1, 1990
and 6 more in the library
Cites 6
- Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe Science August 16, 1968
- Stereospecific binding ofd-lysergic acid diethylamide (LSD) to brain membranes: Relationship to serotonin receptors Brain Research September 1, 1975
- High-affinity 3H-serotonin binding to caudate: inhibition by hallucinogens and serotoninergic drugs. Psychopharmacology September 15, 1978
- Stereospecific receptor sites for d-lysergic acid diethylamide in rat brain: effects of neurotransmitters, amine antagonists, and other psychotropic drugs. Molecular Pharmacology July 1, 1976
- Psychedelic drugs: steric factors that predict psychotropic activity. Proceedings of the National Academy of Sciences May 1, 1968
and 1 more in the library