Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists.
Martin Hansen, Karina Phonekeo, James S Paine, Sebastian Leth-Petersen, Mikael Begtrup, Hans Bräuner-osborne, Jesper L. Kristensen
ACS Chemical Neuroscience March 19, 2014 DOI: 10.1021/cn400216u (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Receptor binding and functional assays |
| Topics | Serotonin |
| Keywords | Receptor pharmacology Medicinal chemistry Serotonin receptors Drug discovery |
| Citations | 125 |
| Key findings | N-benzyl substitution of phenethylamine psychedelics yields compounds with subnanomolar 5-HT2A receptor affinity and high functional selectivity, including one compound with over 400-fold selectivity for 5-HT2A over 5-HT2C. |
Abstract
N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
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 70
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology December 1, 2015
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
- Pharmacological profile of novel psychoactive benzofurans British Journal of Pharmacology March 13, 2015
and 65 more in the library
Cites 16
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology December 1, 2011
- Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later Journal of Psychopharmacology May 30, 2008
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