ACS chemical neuroscienceJan 19, 2024

How a Large Chemical Change Affects Psychedelic Phenethylamine’s Binding and Action on 5-HT2 Brain Receptors

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 6, 2026

Abstract

The introduction of dibenzo,furylymethyl groups on the amine nitrogen of 2C-B resulted in compounds exhibiting up to 40-fold higher affinity at certain serotonin receptors.

Substituents at the 1-, 2-, or 3-position on the amino group decreased affinity and activity at serotonin receptors.
4-position substitutions typically enhanced affinity for all three serotonin receptor subtypes.
Compounds showed 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively.
All derivatives acted as relatively weak partial agonists at the 5-HT2A and 5-HT2C receptors, primarily in the low micromolar range.
Full or nearly full agonist activity was observed at the 5-HT1A receptor.
Molecular docking simulations indicated that the dibenzofuryl moiety penetrates deeply into the receptor's binding site, influencing activation.

Simplified

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HTserotonin receptors. To probe the sensitivity of this effect to substantially larger-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[,]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HTreceptors. Substitution through the 4-position usually favored affinity for all three 5-HTreceptor subtypes with compoundexhibiting 10- and 40-fold higher affinities at the 5-HTand 5-HTreceptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HTR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HTsubtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HTthan the 5-HTreceptor, interacting with the Trp336toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky-substituent on a phenethylamine 5-HTreceptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gprotein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HTreceptor, somewhat higher efficacy at the 5-HTsubtype, and full or nearly full efficacy at the 5-HTsubtype. 2 2A/2C2 2A2C2A2C2A2C2q2A2B2C N b d N5 6.48

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How a Large Chemical Change Affects Psychedelic Phenethylamine’s Binding and Action on 5-HT2 Brain Receptors

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