Synthesis and serotonin receptor affinities of a series of enantiomers of .alpha.-methyltryptamines: evidence for the binding conformation of tryptamines at serotonin 5-HT1B receptors
David Nichols, D. H. Lloyd, Michael P. Johnson, Andrew J. Hoffman
Journal of Medicinal Chemistry July 1, 1988 DOI: 10.1021/jm00402a026 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat frontal cortex homogenates |
| Topics | Serotonin |
| Keywords | Enantiomer Tryptamines Stereochemistry Ethylamine Indole test Imine Benzylamine Receptor |
| Citations | 46 |
| Key findings | Enantioselectivity at serotonin receptor subtypes varied with aromatic substituents: for 5-hydroxy or 5-methoxy AMTs the S enantiomer had higher or equal affinity, while for 4-oxygenated AMTs selectivity reversed and affinity did not improve over unsubstituted compounds. |
Abstract
A procedure for the preparation of optically pure alpha-methyltryptamines (AMTs) from substituted indoles was developed. The key step in the sequence was the reductive amination of substituted indole-2-propanones with the commercially available pure enantiomers of alpha-methylbenzylamine, followed by the chromatographic separation of the resulting pair of diastereomeric amines by preparative centrifugal (Chromatotron) chromatography. Catalytic N-debenzylation then afforded the pure AMT enantiomers. Optical purity was established by chiral HPLC analysis of the 2-naphthoylamide derivatives. An improved procedure for the preparation of indole-2-propanones was also developed. To probe structure-activity relationships of serotonin receptors, affinities of the alpha-methyltryptamine enantiomers were then measured at the 5-HT2 antagonist receptor subtype, with displacement of [3H]ketanserin, and were estimated at the 5-HT1B receptor, with displacement of [3H]serotonin, respectively, in rat frontal cortex homogenates. Enantioselectivity at the receptor subtypes varied, depending on aromatic substituents. For a 5-hydroxy or 5-methoxy, the S enantiomer had higher affinity or was equipotent to the R enantiomer. This selectivity at [3H]serotonin binding sites was reversed for 4-oxygenated alpha-methyltryptamines, where a 4-hydroxy or 4-methoxy did not enhance affinity over the unsubstituted compounds. These results can be explained, for the [3H]serotonin displacement data, if the binding conformation is one where the ethylamine side chain is trans and lying in a plane perpendicular to the indole ring plane.
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 8
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
- [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
- An analysis of the synthetic tryptamines AMT and 5-MeO-DALT: emerging 'Novel Psychoactive Drugs'. Bioorganic & Medicinal Chemistry Letters June 1, 2013
- Patterns of presentation and clinical toxicity after reported use of alpha methyltryptamine in the United Kingdom. A report from the UK National Poisons Information Service Clinical Toxicology February 28, 2014
- Synthesis and In Vitro Profiling of Psilocin Derivatives: Improved Stability and Synthetic Properties Journal of Medicinal Chemistry March 20, 2025
and 3 more in the library